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Chemopreventive Activity of Vitamin E in Breast Cancer: A Focus on γ- and δ-Tocopherol

by 1,2 and 1,2,3,*
Department of Chemical Biology, Ernest Mario School of Pharmacy, 164 Frelinghuysen Road, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
Author to whom correspondence should be addressed.
Nutrients 2011, 3(11), 962-986;
Received: 29 September 2011 / Revised: 20 October 2011 / Accepted: 3 November 2011 / Published: 14 November 2011
(This article belongs to the Special Issue Diet and Cancer Prevention)


Vitamin E consists of eight different variants: α-, β-, γ-, and δ-tocopherols (saturated phytyl tail) and α-, β-, γ-, and δ-tocotrienols (unsaturated phytyl tail). Cancer prevention studies with vitamin E have primarily utilized the variant α-tocopherol. To no avail, a majority of these studies focused on variant α-tocopherol with inconsistent results. However, γ-tocopherol, and more recently δ-tocopherol, have shown greater ability to reduce inflammation, cell proliferation, and tumor burden. Recent results have shown that γ-enriched mixed tocopherols inhibit the development of mammary hyperplasia and tumorigenesis in animal models. In this review, we discuss the possible differences between the variant forms, molecular targets, and cancer-preventive effects of tocopherols. We recommend that a γ-enriched mixture, γ- and δ-tocopherol, but not α-tocopherol, are promising agents for breast cancer prevention and warrant further investigation.
Keywords: vitamin E; tocopherols; breast cancer; estrogen receptor (ER); peroxisome proliferator activated receptor γ (PPARγ); nuclear factor (erythroid-derived 2)-like 2 (Nrf2); anti-inflammatory; cell proliferation; apoptosis; case-control studies vitamin E; tocopherols; breast cancer; estrogen receptor (ER); peroxisome proliferator activated receptor γ (PPARγ); nuclear factor (erythroid-derived 2)-like 2 (Nrf2); anti-inflammatory; cell proliferation; apoptosis; case-control studies

1. Tocopherols

Due to its antioxidant properties, dietary intake of vitamin E, a fat-soluble vitamin, has been suggested to reduce cancer risk [1]. Vitamin E consists of eight different forms which include four tocopherols (with a saturated phytyl tail) and four tocotrienols (with an unsaturated isoprenoid side chain), designated as α, β, γ, and δ variants (Figure 1) [2].
Figure 1. Chemical structures of α-, β-, γ-, and δ-tocopherols.
Figure 1. Chemical structures of α-, β-, γ-, and δ-tocopherols.
Nutrients 03 00962 g001
α-Tocopherol is known as the “classic” vitamin E, because of its superior activity over the other tocopherols in the classic fertility restoration assay [3]. α-Tocopherol is most commonly found in wheat germ, almond, and sunflower oil [4]. However, γ-tocopherol is more prominent than α-tocopherol in the American diet and is found in vegetable oils such as soybean, corn, and cottonseed [5]. δ-Tocopherol is primarily found in soybean and castor oils, and to a lesser extent, in wheat germ oil [6]. A tocopherol mixture containing 58% γ-tocopherol, 24% δ-tocopherol, 13% α-tocopherol, and 0.5% β-tocopherol (γ-TmT) can be easily available as a by-product of refining vegetable oil [7,8]. Tocotrienols are consumed more readily in East-South Asian diets, and found primarily in palm and annatto oils [9,10]. Since tocopherols are the main components of vitamin E in the American diet, this review will focus on tocopherols. The first non antioxidant function of vitamin E determined that α-tocopherol inhibited the activity of smooth muscle proliferation and protein kinase C [11,12]. Since then, three proteins have been identified to specifically bind to tocopherols: α-tocopherol transfer protein (α-TTP), tocopherol-associated protein (TAP), and tocopherol-binding protein (TBP). α-TTP is a 30-35 kDa protein and found in the liver [13] which preferentially transfers α-tocopherol from the liver to the blood [14]. The relative affinities of α-TTP for the variants of vitamin E as determined in vitro were 100% for α-tocopherol, 38% for β-tocopherol, 9% for γ-tocopherol, 2% for δ-tocopherol, and 12% for α-tocotrienol [15]. Thus, the major tocopherol found in human blood and tissues is α-tocopherol [3]. Similar to α-TTP, TAP is also a cystolic lipid-binding and transfer protein. TAP is a 46-kDa protein and has the highest levels in the liver > prostate > whole brain > spinal cord > kidney > mammary gland > stomach [16]. TBP was initially found in rat liver and heart is an approximately 15 kDa cystolic protein [17] and later in human placenta [18]. TBP is involved in intracellular transport and metabolism for α-tocopherol [19].
In the liver, vitamin E is metabolized to chromanol metabolites via the hepatic protein, cytochrome P450 4F2. CYP4F2 catalyzes the initial step in the vitamin E-ω-hydroxylase pathway followed by β-oxidation, which removes 2 carbons from the side chain in each cycle ending in the short chain metabolite, carboxyethyl hydroxychromans (CEHC) [14,20]. Since α-tocopherol is preferentially transferred to the blood by α-TTP, γ-tocopherol and δ-tocopherol are more readily metabolized in the liver [14].
Interestingly, higher concentrations of α-tocopherol may decrease the level of γ-tocopherol in the serum [21,22]. This may be unfavorable since γ-tocopherol has demonstrated significantly greater anti-inflammatory and anti-tumor activity than α-tocopherol in several different animal models of colon, breast, and prostate cancer [22,23,24,25,26,27]. More specifically, γ-tocopherol is more effective in inhibiting the activity of cyclooxygenase-2 (COX-2) [23,28] and trapping reactive nitrogen species than α-tocopherol [23,28,29,30,31,32].
The stability of tocopherol and nitrogen species derivative depends on the structure of the chromanol ring [32]. The tocopherols with a free 5 position on the chromanol ring (γ- and δ-tocopherol) are expected to react with nitrogen species forming C-nitroso derivatives at this position [32]. Both α-tocopherol and γ-tocopherol react with nitrogen dioxide NO2; α-tocopherol forms an intermediate tocopheroxide analogue while γ-tocopherol may form nitric oxide (NO) or a stable nitro derivative (5-nitro-γT) [32]. α-Tocopherol is trimethylated, and consequently, the nitrosating agent only has the possibility to add to the para-position on the chromanol ring of α-tocopherol, forming a highly unstable compound and may form toxic N-nitroso-derivatives from amines [32]. In addition, α-tocopherol may react with nitrous acid to yield α-tocopherol quinone and nitrogen monoxide gas [33]. This may lead to highly instable derivatives which may act as nitrosation catalysts for secondary amines. The high hydrogen donation ability by α-tocopherol may cause undesirable side effects, such as pro-oxidant and toxic nitro derivatives [34].
Tocopherols are recognized for their inhibition of lipid oxidation [35]. The antioxidant properties are mostly due to the phenolic hydrogens in the chromanol ring that are donated to lipid free radicals [36]. α-Tocopherol is trimethylated at the 5-, 7-, and 8-positions on the chromanol ring, γ-tocopherol is dimethylated at 7- and 8-positions, and δ-tocopherol is monomethylated at the 8-postion on the chromanol ring. The structural difference in the chromanol ring may be responsible for the difference in activity of each individual tocopherol form. The ortho-positions (positions 5 and 7) for the methyl groups on the chromanol ring enhance the antioxidant properties of tocopherols and increases the solubility in lipid substrates [33]. Thus, α-tocopherol with two ortho-methyl groups is expected to be a more potent hydrogen donor than either γ-tocopherol (one ortho methyl group) and δ-tocopherol (zero ortho methyl group) [33]. Although α-tocopherol may be a better antioxidant, α-tocopherol consequently has a greater capacity than γ-tocopherol and δ-tocopherol to act as a prooxidant when present in high concentrations in vegetable oils, and with transition metal ions, lipid peroxides, and other oxidizing agents [33,34].
α-Tocopherol has been the most widely studied form of vitamin E for the prevention and treatment of cancer [37,38,39,40]. Although the biological effects of α-tocopherol have been investigated over many decades, our current understanding of its role in inhibiting breast carcinogenesis remains incomplete [41]. The structural difference of the individual tocopherols plays a role in the variance of antioxidant properties, lipophilicity, and the ability to trap reactive nitrogen species (RNS). Both γ- and δ-tocopherol, but not α-tocopherol, show promise as chemopreventive agents in animal models [7,42,43]. In addition, γ-TmT is a mixture of tocopherols enriched with γ-tocopherol and is readily available and inexpensive, while individual variants remain expensive to purify. As a result, γ-TmT may be more practical rather than individual tocopherols for the prevention of breast cancer.

2. Subtypes of Breast Cancer

Breast cancer is one of the most common malignancies affecting women and is the second leading cause of cancer death in women [44]. The etiology and pathogenesis of breast cancer remains poorly understood. Breast cancer is a heterogeneous disease that can be classified into subtypes based on immunohistochemical markers. The subtypes are: estrogen receptor (ER) positive luminal A, ER positive luminal B, human epidermal growth factor receptor-2 positive (HER2 positive), and basal-like [45].

2.1. Estrogen Receptor (ER) Positive

Estrogen receptor positive tumors are classified as a luminal subtype of breast cancer and are reported in 60-70% of cases [45]. Luminal tumors activate ER-responsive genes, other genes that encode characteristic proteins of luminal epithelial cells of origin, and express luminal cytokeratin 8/18 [45]. Luminal A subtype is either ER positive or progesterone receptor (PR) positive but is negative for HER2. Luminal B subtype can be classified as ER positive or PR positive and is positive for HER2 [46]. The prognosis for luminal A is better than luminal B and typically responds more effectively to selective estrogen receptor modulators, such as tamoxifen [45].
Estrogens have been implicated in breast cancer; however, the mechanism of action still remains unclear. One theory suggests that the mechanism is dependent on the activation of the ER. Estrogen induces breast cancer through stimulation of cellular proliferation, resulting in more opportunities for accumulation of genetic damages leading to carcinogenesis [47]. Another possible mechanism of action may be through the metabolism of estrogen, which may induce oxidative stress and play a key role in mammary cancer development [48,49]. 17β-Estradiol and estrone are continuously interconverted by 17β-estradiol hydroxysteroid dehydrogenase (or 17β-oxidoreductase) and are the two major endogenous estrogens. The carbon position of the estrogen molecules that are hydroxylated differs among various tissues in the body and each reaction is probably catalyzed by various CYP enzymes. For example, estrogen may be metabolized by CYP 1A1 to form 2-hydroxyestradiol (2-OHE2) or by CYP 1B1 to form 4-hydroxyestradiol (4-OHE2). These catechols may be methylated by a phase II enzyme, catechol o-methyltransferase (COMT), and excreted out of the body [50]. The 2-OHE2 metabolite is rapidly methylated by COMT, while the 4-OHE2 metabolite is methylated more slowly and thus highly genotoxic [49]. If catechol estrogens are not conjugated (mostly 4-OHE2), it may lead to the formation of semiquinones and subsequently quinones, both of which are electrophiles capable of covalently binding to nucleophilic groups on DNA which may form DNA-adducts [47]. The protective phase II enzyme, NAD(P)H dehydrogenase, quinone 1 (NQO1), catalyzes the reduction of quinones back to catechol estrogens [51].
Under normal conditions, reactive oxygen species (ROS) or RNS are neutralized by detoxifying and antioxidant enzymes [43]. Oxidative stress and/or electrophilic stress during redox cycling of catechol estrogens could contribute to nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation. The estrogen metabolites, 4-OHE1, 4-OHE2, and 2-OHE2 were capable of activating Nrf2, while estradiol did not [52]. This suggests that a catechol structure is required for activation of Nrf2. Estrogen metabolites may exert DNA mutations from ROS or DNA mutations which may lead to the accumulation of genomic alterations essential for mammary tumorigenesis [47]. In one study, 49 women without breast cancer were observed with larger amounts of 2-OHE2 than 4-OHE2 [53]. The 28 women with breast carcinoma expressed 4-OHE2 levels that were 3.5 times more abundant than 2-OHE2 [53]. This supports the finding that estrogen and its metabolites, mainly 4-OHE2, may be carcinogenic agents in breast epithelial cells [53].

2.2. Human Epidermal Growth Factor Receptor 2 (HER2)

HER2 amplification and overexpression has been reported in 18-25% of human breast cancers [54]. HER2 positive breast cancer can be characterized as HER2 positive, negative for ER, and poor differentiation [55]. The prognosis for HER2 positive is worse than luminal breast cancer. HER2 positive breast cancer may be treated with monoclonal antibodies such as trastuzumab (binds to domain IV on the HER2 receptor); however, there are HER2 positive tumors that are resistant to trastuzumab treatment [55]. Other treatments include monoclonal antibody pertuzumab (binds to domain II of the HER2 receptor) [56], trastuzumab antibody conjugated with mertansine (DM1), which is internalized and exerts its cytotoxic effects inside the cell [57], tyrosine kinase inhibitors [58], and HSP90 inhibition which leads to proteasomal degradation [59].
HER2 is a member of the epidermal growth factor (ErbB) family of transmembrane receptors which are potent mediators of normal cell growth and development [60]. The ErbB family is classified as a tyrosine kinase receptor and consists of EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). The structure consists of an extracellular domain at which the ligand binding occurs, the α-helical transmembrane segment, and the intracellular protein tyrosine kinase domain [61]. ErbB receptors normally exist as inactive monomers until a ligand initiates a conformational change to induce dimerization with another receptor. HER2 is unique in the fact that it already possesses an active tyrosine kinase domain and has no direct ligand while HER3 lacks an intrinsic tyrosine kinase activity and cannot form homodimers with itself [62]. The HER2-HER3 heterodimer is considered the most potent and active ErbB dimer [63,64,65]. HER2 signaling leads to oncogenic cell survival and proliferation through the MAPK pathway [66]. HER3 can directly bind to the p85 subunit of PI3K to stimulate the PI3K-Akt pathway while EGFR and HER2 have additional activation steps by binding to the adaptor proteins GRB2 (growth factor receptor bound 2) and GAB1 (GRB2-associated binding protein 1) [67]. Thus, the HER2-HER3 dimer leads to the MAPK pathway to stimulate angiogenesis, proliferation, and PI3K-Akt pathway to promote cell survival, suppression of apoptosis, and cell cycle control [66].

2.3. Basal-Like

Basal-like subtype is characterized by ER and HER2 negativity, high expression of basal stratified epithelial cytokeratins 5, 6, and 17, and expression of proliferation-related genes [45,68]. The prognosis of basal-like tumors is poor, with frequent mutations in TP53 [69]. BRCA1 mutations are also generally basal-like breast tumors [68,69]. The incidence of basal-like breast cancer may be increased by both race and age, where premenopausal African American women developed basal-like tumors (39%) compared to postmenopausal African American women (14%) and non-African American women (16%) [70]. In addition, microarray analysis revealed that younger patients of any ethnicity tend to form basal-like tumors over other types [69,70].

3. Cellular Events and Molecular Targets in Breast Cancer

Each subtype of breast cancer responds differently to current treatments and therapy. To date, there is limited in vitro, in vivo, and human data which connect individual tocopherols for prevention or treatment for each subtype of breast cancer. Chemoprevention is an approach to prevent cancer before a series of genetic and epigenetic events establish which otherwise could lead to malignancies. Thus, prevention of breast cancer is essential, and the success of prevention strategies depends on understanding the molecular mechanism of breast cancer initiation and progression. The mechanisms of anti-cancer activity of tocopherols have been investigated for many years [39,71,72] and can be summarized as follows: (a) inhibition of ER (b) increasing peroxisome proliferator activated receptor γ (PPARγ) expression and activity, (c) induction of Nrf2, (d) antioxidative and anti-inflammatory activities, and (e) induction of apoptosis [28,39,43,72,73].

3.1. Estrogen Receptor (ER)

ER is a nuclear receptor that stimulates cell growth and proliferation [48]. The ER is a ligand-activated transcription factor that, when bound to estrogen, induces a conformational change that allows dimerization and binding to estrogen response element sequences. There are two known ER receptors: ERα and ERβ. The DNA binding domain of the two different receptors is highly homologous while the ligand binding domain is 60% homologous [74]. ERα and ERβ are both present in breast tissue, but the ratio of ERα to ERβ is increased in breast tumors [74]. The role of ERβ in breast tumorigenesis is not well understood. Some studies have shown that activation of ERβ in breast cancer cell lines inhibits cell growth, and the dimerization of ERβ with ERα silences the growth-promoting effects of ERα [74,75].
Vitamin E has been shown to inhibit ER-positive cell proliferation and work as antagonists of estrogen signaling in MCF-7 and T47D breast cancer cells [73]. MCF-7 cells were treated with γ-TmT, and the expression of ERα was down-regulated [7]. In mammary tumors, ERα mRNA and protein levels were down-regulated by the treatment of γ-TmT [7]. Administration of γ-TmT reduced ERα mRNA and protein levels in hyperplastic mammary tissues in estrogen-treated ACI rats, while mRNA levels of ERβ were increased [76]. Furthermore, dietary γ-TmT decreased circulating levels of E2 in the serum, suggesting that γ-TmT may modify the response to estrogen [76].

3.2. Peroxisome Proliferator Activated Receptor γ (PPARγ)

Belonging to the nuclear hormone receptor superfamily, PPAR comprises of 3 subtypes (α, γ, and δ) which are ligand-regulated transcription factors [77]. PPARγ is known to be involved in fatty acid uptake and transport and acts to control inflammation by inducing apoptosis and inhibiting cell proliferation cell survival [78,79]. PPARγ signaling is connected to the inhibition of inflammatory markers (COX-2, cytokines, and inducible nitric oxide synthase), PI3K/Akt pathway, and angiogenesis while inducing CDK inhibitors, differentiation and apoptosis markers in cancers [79]. Particularly in breast cancer, stimulation of PPARγ increases the degradation of cell cycle genes (Cyclin D1), interferes with estrogen receptor signaling, and NF-κB signaling cascades [80,81].
When ligand-activated, PPARγ forms a heterodimer with the retinoid X receptor [78]. A known PPARγ ligand is troglitazone [27], and the chromanol ring of tocopherol is structurally similar. Recently it was thought that tocopherols might function as a PPARγ ligand because of this structural resemblance, but it was shown that γ-tocopherol does not directly bind to PPARγ [81]. Instead, γ-tocopherol induces the formation of 15-S-hydroxyeicosatetraenoic acid, an endogenous PPARγ ligand [81].
Tocopherols, with γ-tocopherol displaying the strongest activity, increased mRNA and protein levels of PPARγ in colon cancer cells [27] and transcriptional activity in keratinocytes cell line [82] (Table 1). In MCF-7 and T47D breast cancer cells, γ-TmT, γ-tocopherol, and more strongly δ-tocopherol enhance the transactivation of PPARγ [7]. Comparable to the finding in the N-methyl-N-nitrosourea (NMU)-induced breast cancer model in Sprague-Dawley rats [7], PPARγ was increased at both the protein and mRNA level in the mammary gland of ACI rats when treated with γ-TmT while ERα expression was decreased [76]. Since PPARγ transactivation can be suppressed by ERα binding to the PPAR response element [83], the inhibition of ERα expression by tocopherols may result in the activation of PPARγ. Thus, tocopherols may indirectly activate PPARγ, and possibly through this pathway may interfere with ERα expression, inhibit cell cycle progression and induce apoptosis to prevent breast cancer.
Table 1. Tocopherols induce PPARγ levels.
Table 1. Tocopherols induce PPARγ levels.
TocopherolCell type/Cancer modelResultReferences
γ-TocopherolColon cancer cells (SW 480)↑ PPARγ mRNA and protein level[27]
γ-TocopherolKeratinocytes cells (NCTC 2544)↑ PPARγ mRNA levels[82]
γ-TmT, γ-Tocopherol, δ-TocopherolBreast cancer cells (MCF-7 and T47D)↑ PPARγ transactivation[7]
γ-TmTNMU-induced mammary tumors in female Sprague-Dawley rats↑ PPARγ mRNA and protein level[7]
γ-TmTEstrogen-induced mammary hyperplasia in female ACI rats↑ PPARγ mRNA and protein level[76]

3.3. Nuclear Factor (Erythroid-Derived 2)-Like 2 (Nrf2)

Nrf2 is a transcription factor that is a key regulator of cellular antioxidant and detoxification enzymes [84]. Initially, Nrf2 activity is inhibited when bound to kelch-like-ECH-associated protein 1 (KEAP1) in the cytoplasm and is marked for degradation through the proteasomal pathway [84]. Under oxidative stress or chemopreventive agents, KEAP1 undergoes covalent modification which allows the release and the consequential activation of Nrf2 [84,85,86]. As a result, Nrf2 translocates into the nucleus, dimerizes with small Maf proteins, and binds to the antioxidant-responsive element (ARE) to stimulate gene expression of antioxidant enzymes (thioredoxin, superoxide dismutase[SOD], catalase, glutathione peroxidase, and heme oxygenase-1[HO-1]), and phase II detoxification enzymes (glutathione s-transferases[GST], UDP-glucuronosyltransferases, sulfotransferases, and NQO1) [43,84,85,86,87]. As a result, these detoxifying and antioxidant enzymes protect cells from neoplastic transformation by maintaining oxidative stress homeostasis [43,88]. A loss of Nrf2 may lead to a decrease in cellular defense against oxidative stress which may result in tumorigenesis [89].
In human retinal pigment epithelial cells, pretreatment with α-tocopherol inhibited ROS generation, increased Nrf2 expression, and, induced phase II enzymes (glutamate cysteine ligase, NQO1, HO-1, GST, and SOD) [90] (Table 2). The expression of Nrf2 was suppressed in prostate tumors [91], and treatment with γ-TmT upregulated the expression of Nrf2 and detoxifying enzymes, and inhibited tumor development in TRAMP mice [43,91]. We recently demonstrated that when estrogen-treated ACI rats were administered γ-TmT diet, the protein expression level of Nrf2 was increased in the mammary gland and liver, and phase II enzymes were increased in the liver [92]. The mRNA expressions of phase II detoxifying enzymes were induced in the mammary gland and liver by γ-TmT treatment. This may indicate that γ-TmT induces the transcription of Nrf2-ARE-target genes and exhibits protective defense against estrogen induced oxidative stress.
Table 2. Tocopherols induce Nrf2 and related antioxidant enzymes.
Table 2. Tocopherols induce Nrf2 and related antioxidant enzymes.
TocopherolCell type/Cancer modelResultReferences
α-TocopherolHuman retinal pigment epithelial cells (ARPE-19)↑ Nrf2 protein levels, ↑ glutamate cysteine ligase, NQO1, HO-1, GST, SOD[90]
γ-TmTProstate carcinogenesis in TRAMP male mice↑ Nrf2 protein levels, ↑ GSTm1, UGT1A1, HO-1, catalase, SOD, glutathione peroxidase,[43]
γ-TmTEstrogen-induced mammary hyperplasia in female ACI rats↑ Nrf2 protein levels[92]

3.4. Cell Proliferation and Apoptosis

Apoptosis is defined as programmed cell death with distinct morphological and biochemical changes [93,94]. During the earlier stages, the apoptotic cell shrinks in volume and the nuclear DNA condenses, while the cellular membrane remains intact [94,95]. Apoptotic bodies are formed and the tightly packed organelles leave the cell through “budding” [96]. There are two distinct apoptotic pathways: extrinsic and intrinsic [97]. Caspases have proteolytic activity and are able to cleave proteins. There are ten major caspases with three main sub groups: initiators (−2, −8, −9, and −10), effectors (−3, −6, and −7), and inflammatory (−1, −4, and −5) [98,99].
In breast, colon, lung, and prostate cancer cell lines, γ-tocopherol was shown to be more effective at inhibiting cell growth than α-tocopherol [7,25,26,100]. Our in vitro data showed that treatment with γ-TmT, γ-, and δ-tocopherol inhibited cell proliferation in MCF-7 breast cancer cells in a dose-dependent manner, while α-tocopherol did not [7]. In addition, a colony growth inhibition assay utilizing MDA-MB-435 breast cancer cells showed that γ- and δ-tocopherol showed potential to inhibit colony formation, whereas α‑tocopherol was not active [39].
γ-Tocopherol has been shown to induce apoptosis in breast, colon, and prostate cancer cells [26,100,101,102,103] (Table 3). Yu et al. showed that apoptosis was induced by δ-tocopherol in MCF-7 and MDA-MB-435 breast cancer cells [102]. Furthermore, γ-tocopherol, but not α-tocopherol, induced cleaved-caspase 8 and 9 in MDA-MB-435 human breast cancer cells [103]. In one xenograft model, when treated with γ-tocopherol, tumor growth was inhibited, and TUNEL assay determined that there was an increase in apoptotic cells [22]. γ-Tocopherol and to a greater extent, δ-tocopherol, were shown to inhibit tumor growth more strongly than α-tocopherol in a lung xenograft model, while α-tocopherol did not [42].
Table 3. Tocopherols inhibit cell proliferation and induce apoptosis.
Table 3. Tocopherols inhibit cell proliferation and induce apoptosis.
TocopherolCell type/Cancer modelResultReferences
γ-TocopherolProstate cancer cells (LNCaP and PC-3) and lung cancer cells (A549)↓ Proliferation[101]
γ-Tocopherol and combination of γ-Tocopherol and δ-TocopherolProstate cancer cells (LNCaP)↑ Apoptosis[101]
γ-TocopherolColon cancer cells (SW480, HCT-15, HCT-116, HT-29)↓ Proliferation, ↑ Apoptosis[100]
γ-TocopherolProstate cancer cells (LNCaP)↓ Proliferation, ↑ Apoptosis[101]
δ-TocopherolBreast cancer cells (MCF-7 and MDA-MB-435)↑ Apoptosis[102]
γ-TocopherolBreast cancer cells (MCF-7 and MDA-MB-435) and murine 66cl-4↓ Proliferation, ↑ Apoptosis[103]
γ-TocopherolBresat cancer MDA-MB-231 xenograft in nu/nu mice↑ Apoptosis[22]
γ-Tocopherol, δ-TocopherolLung cancer H1299 xenograft in nu/nu mice↑ Apoptosis[42]
γ-TmTNMU-induced mammary tumors in female Sprague-Dawley rats↓ Proliferation[104]
γ-TmTNMU-induced mammary tumors in female Sprague-Dawley rats↑ Apoptosis[7]
γ-Tocopherol, δ-Tocopherol, γ-TmTNMU-induced mammary tumors in female Sprague-Dawley rats↑ Apoptosis[105]
γ-TmTEstrogen-induced mammary hyperplasia in female ACI rats↓ Proliferation, ↑ Apoptosis[76]
In vivo models showed that mammary tumor growth and burden was decreased by γ-TmT diet [7,104]. Proliferating cell nuclear antigen (PCNA) was decreased in mammary hyperplasia [76] and in mammary tumors when administered γ-TmT [104]. Administration of γ-TmT increased the levels of cleaved-caspase 3 increased in mammary hyperplasia [76] and in mammary tumors [7]. Furthermore, γ-TmT and individual tocopherols were administered to Sprague-Dawley rats which were induced with NMU carcinogen; treatment with γ-TmT, γ-, and δ-tocopherol decreased PCNA levels while increased the levels of cleaved-caspase 3 in mammary tumors, whereas α-tocopherol was not active [105]. At high doses, tocopherols may induce DNA damage leading to apoptosis. There is the possibility of tocopherols, especially α-tocopherol, to act as a pro-oxidant to create ROS or RNS.

3.5. Cyclooxygenase-2 (COX-2) and Anti-Inflammatory Activities

COX-2 is an inducible prostaglandin synthase which is upregulated by growth factors, tumor promoters, and cytokines [106], and responsive to several oncogenes, such as HER2 [107,108]. In inflamed and neoplastic tissues, an increase in prostaglandin synthesis is detected [107]. Around 40% of aggressive human breast cancers are associated with high levels of COX-2 which correlates with large tumor sizes, high proliferation rates, and metastases [108]. Celecoxib, a COX-2 inhibitor, was fed to HER2/neu transgenic mice and found that there was a 50% reduction in mammary prostaglandin E2 (PGE2) levels and delayed tumor onset [109].
Tocopherols are known antioxidants and anti-inflammatory agents, and γ-tocopherol is more effective in inhibiting the activity of COX-2 and trapping reactive nitrogen species than α-tocopherol (Table 4) [23,28,29,30,31,110]. In addition, γ-tocopherol was shown to reduce PGE2 synthesis in macrophages and human epithelial cells [28], and the inhibitory effect was due to the decrease of COX-2 activity [28,111]. In our study, serum levels of PGE2 and 8-isoprostane, a marker of oxidative stress, were reduced when estrogen-induced ACI rats were treated with γ-TmT, and COX-2 levels decreased in the mammary gland when treated with dietary γ-TmT [76]. γ-TmT treatment may reduce inflammation in an estrogen-induced model of mammary hyperplasia and tumorigenesis.
Table 4. Tocopherols decrease COX-2 and RNS.
Table 4. Tocopherols decrease COX-2 and RNS.
TocopherolCell type/Cancer modelResultReferences
γ-TocopherolCarrageenan-induced inflammation in Wistar male rats↓ RNS, ↓ PGE2, ↓ LTB4, ↓ TNF-α[29]
γ-TocopherolMacrophages (RAW264.7) and human epithelial cells (A549)↓ COX-2, ↓ PGE2[28]
γ-TocopherolZymosan-induced acute peritonitis in male Fischer 344 rats↓ RNS[30]
γ-TocopherolHuman plasma↓ RNS, ↓ peroxynitrite[31]
γ-Tocopherol, δ-TocopherolHuman epithelial cells (A549)↓ COX-2[111]
γ-TmTEstrogen-induced mammary hyperplasia in female ACI rats↓ COX-2, ↓ PGE2, ↓ 8-isoprostane[76]

4. Studies on Tocopherols and Human Cancers

4.1. Case-Control and Cohort Studies

There are several case-control, cohort, and intervention studies on vitamin E and human cancers, but our main focus will address breast cancer. Numerous case-control studies utilized vitamin E and 11 studies found a risk reduction [112,113,114,115,116,117,118,119,120,121,122], however, 13 studies did not find an association with breast cancer incidence (Table 5) [123,124,125,126,127,128,129,130,131,132,133,134,135]. In the Shanghai Breast Cancer Study, they suggest that vitamin E supplement may reduce the risk of breast cancer among women who have low dietary intake [122]. To date, 12 cohort studies did not find any relation between vitamin E and prevention of breast cancer risk (Table 6) [136,137,138,139,140,141,142,143,144,145,146,147]. In one cohort study, the European Prospective Investigation into Cancer and Nutrition (EPIC) trial observed that vitamin E did not reduce breast cancer risk, but there was a weak risk reduction in post-menopausal women [145]. While investigating vitamin supplement during breast cancer treatment and survival, Nechuta et al. determined that vitamin E supplementation in the first 6 months after diagnosis may reduce risk of mortality and recurrence [148].
Table 5. Case-control studies of vitamin E and breast cancer risk.
Table 5. Case-control studies of vitamin E and breast cancer risk.
StudyPopulationYearCase/Control aIntake or blood levelsRelative risk (95% CI) for highest vs. lowest levelConclusion
[124]Canada1989-1993223/85Serum or adipose tissue levels of α-T: levels were not specifiedSerum α-T: 0.85 (0.45-1.59)No association
Adipose tissue α-T:1.34 (0.73-2.47)
[125]US1976-1998969/969Serum α-T or γ-T: levels were not specifiedSerum α-T: 0.79 (0.57-1.08)No association
Serum γ-T: 0.96 (0.71-1.30)
[126]US1975-1994244/244 (1974 Study)Serum α-T: 0.91-1.40 mg/dL; 0.99-1.65 mg/dLSerum α-T: 0.94 (0.52-1.73); 0.67 (0.28-1.62)No association
115/115 (1989 Study)Serum γ-T: 0.15-0.32 mg/dL; 0.13-0.34 mg/dLSerum γ-T: 0.70 (0.40-1.23); 0.80 (0.33-1.93)
[127]US1975-199364/64Serum α-T: 1.31 mg/dLα-T: 0.46 (0.23-0.64)No association
Serum γ-T: 0.25 mg/dLγ-T: 0.53 (0.32-0.69)
[113]India Pre-M: 28/23Serum α-T: 38 vs. 25 μmol/LSerum α-T: P < 0.05Risk reduction
Post-M: 29/19Serum γ-T: 30 vs. 25 μmol/LSerum γ-T: p < 0.02
[129]US 27/28Serum α-T: ≤20.5 ~ ≥35 μmol/LSerum α-T: 0.76 (0.10-5.75)No association
Serum γ-T: ≤2.12~ ≥7.573 μmol/LSerum γ-T:0.31 (0.04-1.93)
[130]Greek Pre-M: 270/505Vit E: <5.2 ~ ≥8.6 IU/dayPre-M: 0.50 (0.25-1.02)No association
Post-M: 550/1041Post-M: 0.85 (0.53-1.36)
[114]Finish Pre-M: 119/324Vit E: ≤7 ~ >13 mg/day0.5 (0.2-1.0)Risk reduction
[115]Uruguay 400/405Vit E: 4.7 ~ 9.7 mg/day0.4 (0.26-0.62)Risk reduction
[131]Italian Pre-M: 989/841Vit E: <8.5 ~ 11.7 mg/dayPre-M: 1.27 (0.9-1.78)No association
Post-M: 1577/1745Post-M: 1.16 (0.92-1.46)
[132]US1977-1989105/203Serum α-T: ≤21.6 ~ ≥31.3 μmol/L1.2 (0.5-2.8)No association
[116]Italy Pre-M: 988/843Vit E: levels were not specifiedPre-M: 0.8 (0.7-1.0)Risk reduction
Post-M: 1572/1742Post-M: 0.75 (0.6-0.9)
[117]US 297/311α-T: <6 ~ ≥11 mg/day0.55 (0.34-0.88)Risk reduction
[112]US Pre-M without family history: 224/251α-T: ≤6.3 ~ >10.4 IU/day0.5 (0.2-1.0)Risk reduction
[118]US Post-M: 313/349Vit E: 11 vs. 5.4 mg/day (median)0.4 (0.2-0.9)Risk reduction
[119]Malaysia 57/139Vit E: 6.1 vs. 6.9 mg/day (mean)2.12 (1.00-4.21)Risk reduction
[128]South Korea2004-2006362/362Vit E: 10.6 vs. 11.2 mg/day0.66 (0.41-1.08)No association
[120]Switzerland1993-1999289/442Vit E: 9.4-18.1 mg/day0.49 (0.35-0.71)Risk reduction
[121]Italy1991-19942569/2588Vit E: 7.21-13.43 mg/day0.75 (0.6-0.9)Risk reduction
[123]Germany1998-1999310/353Vit E: 7.1-12.7 mg/day1.08 (0.58-2.03)No association
[122]China1996-1998 and 2002-20043454/3474Vit E: levels not specifiedLow supplemental Vit E: 0.7 (0.5-1.0)Risk reduction
High supplemental Vit E: 1.2 (0.9-1.6)
[133]US1999-20041498/1559 (Non-Hispanic white) 763/877 (Hispanic)α-T: 108-224 mg/dayα-T: 0.87 (0.73-1.03)No association
β-T: 0.3-0.4 mg/dayβ-T: 1.10 (0.89-1.36)
γ-T: 15.9-19.4 mg/dayγ-T: 1.13 (0.89-1.44)
δ-T: 2.94-3.59 mg/dayδ-T: 1.10 (0.89-1.35)
[134]Denmark1993-1997418/394Dietary Vit E: Dietary Vit E: 1.13 (0.61-2.10)No association
4.30-14.8 mg/daySupplemental Vit E: 1.00 (0.96-1.03)
Supplemental Vit E: 0.94-78.23 mg/day
[135]South Korea1999-2000224/250Dietary Vit E: 6.26-12.71 mg/dayDietary Vit E: 0.71 (0.39-1.27)No association
a Pre-menopausal (Pre-M) or postmenopausal (Post-M) women.
Previously, detailed assessments revealed that vitamin E (α-tocopherol) supplements did not protect against breast cancer [149,150]. Recently, Fulan et al. performed a meta-analysis on 38 studies between vitamin E and breast cancer [151]. For case-control studies, dietary vitamin E and total vitamin E reduced breast cancer risk by 18% and 11%, respectively [151]. When the cohort studies were pooled with the case-control studies, dietary vitamin E and total vitamin E both became nonsignificant [151]. Thus, a conclusion remains elusive between breast cancer and vitamin E. The term “vitamin E” is used loosely, and a distinction in these case-control and cohort studies need to clarify which variant of vitamin E is utilized.
Table 6. Cohort studies of vitamin E and breast cancer risk.
Table 6. Cohort studies of vitamin E and breast cancer risk.
StudyPopulationYearCase/Control aIntake or blood levelsRelative risk (95% CI) for highest vs. lowest levelConclusion
[136]Canada1982-1987519/1182α-T: <3 vs. >7 mg/dayα-T: 1.05 (0.65-1.70)No association
[137]Sweden1987-19901271/59036Vit E: 9.3 vs. 3.8 mg/day (median)0.83 (0.6-1.14)No association
[138] Pre-M: 784/53938Vit E: 10 vs. 5 IU/day (median)0.81 (0.64-1.02)No association
[139]Netherlands Post-M: 650/62573Vit E: 19.8 vs. 6.9 mg/day (median)1.25 (0.85-1.85)No association
[140]Finland 88/4697Vit E: levels were not specified1.08No association
[141]US1986570/21782Vit E: 10 vs. 5 mg/day0.81 (0.64-1.02)No association
[142]US1976-19821439/89494Dietary Vit E: <3.9 ~ ≥24.1 IU/dayDietary Vit E: 0.90 (0.77-1.06)No association
Supplemental Vit E: 600 vs. 0 IU/daySupplemental Vit E: 1.01 (0.69-0.49)
[143]Canada 325/628Vit E: ~18 IU/day (median)1.32 (0.85-2.05)No association
[144]US1980-1987Post-M: 344/18586Vit E: <4.3 ~ ≥9.3 mg/day0.86 (0.61-1.21)No association
[145]Europe1992-20007502/334493Vit E: 5.4-19.5 mg/day0.92 (0.77-1.11)No association
[146]US1993-19982879/81926Dietary Vit E: 6.2-9.4 mg/dayDietary Vit E: 1.03 (0.91-1.17)No association
Supplemental Vit E: 0-424 mg/daySupplemental Vit E: 1.01 (0.90-1.14)
[147]US1991-1999Pre-M: 714/90655Vit E: 7-59 mg/dayVit E: 1.13 (0.89-1.43)No association
Dietary Vit E: 6-10 mg/dayDietary Vit E: 1.17 (0.92-1.50)
a Pre-menopausal (Pre-M) or postmenopausal (Post-M) women.

4.2. Intervention Studies

The Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study examined the prevention of lung and other cancers with supplementation of all-racemic-α-tocopherol acetate (50 mg/day) and β-carotene (20 mg/day) daily, which did not have an effect on lung or colorectal cancer [152,153]. However, the ATBC study found that males supplemented with α-tocopherol acetate (50 mg daily) had 32% lower prostate cancer incidence and 41% reduction in prostate cancer deaths [154]. The Physicians’ Health Study II gave supplements of 400 IU of α-tocopherol every other day or 500 mg of vitamin C daily and concluded that neither vitamin E nor C reduced the risk of prostate cancer [155]. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) administered selenium (200 μg/day) and all rac-α-tocopheryl acetate (400 IU/day) and revealed that selenium or vitamin E, alone or in combination, did not prevent prostate cancer [156]. These previous clinical and epidemiological studies have been primarilyutilized α-tocopherol, and not a mixture of tocopherols or other variants of tocopherols for chemoprevention [37,38,39,40].
There have been 3 breast cancer randomized controlled trials (RCT), which administered supplemental natural-source vitamin E (either 400 IU or 600 IU), and concluded that there was no overall benefit of vitamin E supplementation [37,157,158]. Only one RCT specified using the variant α-tocopherol [158], but in most cases, the studies do not identify which variant of vitamin E was utilized. Thus, epidemiological evidence between vitamin E and breast cancer is limited and inconsistent [41]. There are four tocopherols and four tocotrienols that comprise vitamin E, each which differ in chemical structure, bioavailability, and activity. Results will remain inconclusive unless the specific variant is identified for each study.

5. Conclusion

α-Tocopherol has been investigated over many years, while data are lacking for γ- and δ-tocopherols. A γ-enriched mixture of tocopherol is commonly found as a by-product of corn oil and should also be explored. The status of tocopherol as a chemopreventive agent remains unclear due to inconsistent results. In previous case-control and cohort studies, the term vitamin E may be vague, with few studies specifying which variant is utilized. A distinction needs to be addressed to determine the efficacy of each tocopherol variant and its chemopreventive activity. It has been suggested that γ-TmT, γ-tocopherol, and more recently δ-tocopherol may contribute to inhibiting tumor formation. Possible mechanism of actions in inhibiting breast cancer could be: inducing PPARγ expression and as a result reducing the expression of ERα, inducing Nrf2 which consequently reduces inflammation and oxidative stress, and inhibiting cell proliferation while inducing apoptosis. Further investigation is warranted with γ-TmT, γ- and δ-tocopherol in human prevention trials.


This work was supported in part by NIH R03 CA141756, the Trustees Research Fellowship Program at Rutgers, The State University of New Jersey, and from the NIEHS Center Grant P30 ES005022.

Conflict of Interest

The authors declare no conflict of interest.


  1. Taylor, P.R.; Qiao, Y.L.; Abnet, C.C.; Dawsey, S.M.; Yang, C.S.; Gunter, E.W.; Wang, W.; Blot, W.J.; Dong, Z.W.; Mark, S.D. Prospective study of serum vitamin E levels and esophageal and gastric cancers. J. Natl. Cancer Inst. 2003, 95, 1414–1416. [Google Scholar]
  2. Constantinou, C.; Papas, A.; Constantinou, A.I. Vitamin E and cancer: An insight into the anticancer activities of vitamin E isomers and analogs. Int. J. Cancer 2008, 123, 739–752. [Google Scholar]
  3. Brigelius-Flohe, R.; Traber, M.G. Vitamin E: Function and metabolism. FASEB J. 1999, 13, 1145–1155. [Google Scholar]
  4. McLaughlin, P.J.; Weihrauch, J.L. Vitamin E content of foods. J. Am. Diet. Assoc. 1979, 75, 647–665. [Google Scholar]
  5. Traber, M.G. Vitamin E regulatory mechanisms. Annu. Rev. Nutr. 2007, 27, 347–362. [Google Scholar]
  6. Aggarwal, B.B.; Sundaram, C.; Prasad, S.; Kannappan, R. Tocotrienols, the vitamin E of the 21st century: Its potential against cancer and other chronic diseases. Biochem. Pharmacol. 2010, 80, 1613–1631. [Google Scholar]
  7. Lee, H.J.; Ju, J.; Paul, S.; So, J.Y.; DeCastro, A.; Smolarek, A.; Lee, M.J.; Yang, C.S.; Newmark, H.L.; Suh, N. Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-gamma. Clin. Cancer Res. 2009, 15, 4242–4249. [Google Scholar]
  8. Ju, J.; Hao, X.; Lee, M.J.; Lambert, J.D.; Lu, G.; Xiao, H.; Newmark, H.L.; Yang, C.S. A gamma-tocopherol-rich mixture of tocopherols inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice. Cancer Prev. Res. (Phila.) 2009, 2, 143–152. [Google Scholar] [PubMed]
  9. Sen, C.K.; Khanna, S.; Roy, S. Tocotrienols in health and disease: The other half of the natural vitamin E family. Mol. Aspects Med. 2007, 28, 692–728. [Google Scholar]
  10. Tan, B. Tocotrienols: The New Vitamin E., 2010. Available online: (accessed on 15 October 2011).
  11. Boscoboinik, D.; Szewczyk, A.; Azzi, A. Alpha-tocopherol (vitamin E) regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch. Biochem. Biophys. 1991, 286, 264–269. [Google Scholar]
  12. Boscoboinik, D.; Szewczyk, A.; Hensey, C.; Azzi, A. Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C. J. Biol. Chem. 1991, 266, 6188–6194. [Google Scholar] [PubMed]
  13. Murphy, D.J.; Mavis, R.D. Membrane transfer of alpha-tocopherol. Influence of soluble alpha-tocopherol-binding factors from the liver, lung, heart, and brain of the rat. J. Biol. Chem. 1981, 256, 10464–10468. [Google Scholar] [PubMed]
  14. Sontag, T.J.; Parker, R.S. Cytochrome P450 omega-hydroxylase pathway of tocopherol catabolism. Novel mechanism of regulation of vitamin E status. J. Biol. Chem. 2002, 277, 25290–25296. [Google Scholar] [PubMed]
  15. Hosomi, A.; Arita, M.; Sato, Y.; Kiyose, C.; Ueda, T.; Igarashi, O.; Arai, H.; Inoue, K. Affinity for alpha-tocopherol transfer protein as a determinant of the biological activities of vitamin E analogs. FEBS Lett. 1997, 409, 105–108. [Google Scholar]
  16. Zimmer, S.; Stocker, A.; Sarbolouki, M.N.; Spycher, S.E.; Sassoon, J.; Azzi, A. A novel human tocopherol-associated protein: Cloning, in vitro expression, and characterization. J. Biol. Chem. 2000, 275, 25672–25680. [Google Scholar] [PubMed]
  17. Dutta-Roy, A.K.; Gordon, M.J.; Leishman, D.J.; Paterson, B.J.; Duthie, G.G.; James, W.P. Purification and partial characterisation of an alpha-tocopherol-binding protein from rabbit heart cytosol. Mol. Cell Biochem. 1993, 123, 139–144. [Google Scholar]
  18. Gordon, M.J.; Campbell, F.M.; Dutta-Roy, A.K. alpha-Tocopherol-binding protein in the cytosol of the human placenta. Biochem. Soc. Trans. 1996, 24, 202S. [Google Scholar]
  19. Gordon, M.J.; Campbell, F.M.; Duthie, G.G.; Dutta-Roy, A.K. Characterization of a novel alpha-tocopherol-binding protein from bovine heart cytosol. Arch. Biochem. Biophys. 1995, 318, 140–146. [Google Scholar]
  20. Birringer, M.; Pfluger, P.; Kluth, D.; Landes, N.; Brigelius-Flohe, R. Identities and differences in the metabolism of tocotrienols and tocopherols in HepG2 cells. J. Nutr. 2002, 132, 3113–3118. [Google Scholar]
  21. Huang, H.Y.; Appel, L.J. Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J. Nutr. 2003, 133, 3137–3140. [Google Scholar]
  22. Yu, W.; Jia, L.; Park, S.K.; Li, J.; Gopalan, A.; Simmons-Menchaca, M.; Sanders, B.G.; Kline, K. Anticancer actions of natural and synthetic vitamin E forms: RRR-alpha-tocopherol blocks the anticancer actions of gamma-tocopherol. Mol. Nutr. Food Res. 2009, 53, 1573–1581. [Google Scholar]
  23. Jiang, Q.; Christen, S.; Shigenaga, M.K.; Ames, B.N. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attentio. Am. J. Clin. Nutr. 2001, 74, 714–722. [Google Scholar]
  24. Dietrich, M.; Traber, M.G.; Jacques, P.F.; Cross, C.E.; Hu, Y.; Block, G. Does gamma-tocopherol play a role in the primary prevention of heart disease and cancer? A review. J. Am. Coll. Nutr. 2006, 25, 292–299. [Google Scholar]
  25. Gysin, R.; Azzi, A.; Visarius, T. Gamma-tocopherol inhibits human cancer cell cycle progression and cell proliferation by down-regulation of cyclins. FASEB J. 2002, 16, 1952–1954. [Google Scholar]
  26. Jiang, Q.; Wong, J.; Fyrst, H.; Saba, J.D.; Ames, B.N. gamma-Tocopherol or combinations of vitamin E forms induce cell death in human prostate cancer cells by interrupting sphingolipid synthesis. Proc. Natl. Acad. Sci. USA 2004, 101, 17825–17830. [Google Scholar]
  27. Campbell, S.E.; Stone, W.L.; Whaley, S.G.; Qui, M.; Krishnan, K. Gamma (gamma) tocopherol upregulates peroxisome proliferator activated receptor (PPAR) gamma (gamma) expression in SW 480 human colon cancer cell lines. BMC Cancer 2003, 3, 25. [Google Scholar] [CrossRef] [PubMed]
  28. Jiang, Q.; Elson-Schwab, I.; Courtemanche, C.; Ames, B.N. Gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cell. Proc. Natl. Acad. Sci. USA 2000, 97, 11494–11499. [Google Scholar]
  29. Jiang, Q.; Ames, B.N. Gamma-tocopherol, but not alpha-tocopherol, decreases proinflammatory eicosanoids and inflammation damage in rat. FASEB J. 2003, 17, 816–822. [Google Scholar]
  30. Jiang, Q.; Lykkesfeldt, J.; Shigenaga, M.K.; Shigeno, E.T.; Christen, S.; Ames, B.N. Gamma-tocopherol supplementation inhibits protein nitration and ascorbate oxidation in rats with inflammation. Free Radic. Biol. Med. 2002, 33, 1534–1542. [Google Scholar]
  31. Christen, S.; Woodall, A.A.; Shigenaga, M.K.; Southwell-Keely, P.T.; Duncan, M.W.; Ames, B.N. Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: Physiological implications. Proc. Natl. Acad. Sci. USA 1997, 94, 3217–3222. [Google Scholar]
  32. Cooney, R.V.; Franke, A.A.; Harwood, P.J.; Hatch-Pigott, V.; Custer, L.J.; Mordan, L.J. Gamma-tocopherol detoxification of nitrogen dioxide: Superiority to alpha-tocopherol. Proc. Natl. Acad. Sci. USA 1993, 90, 1771–1775. [Google Scholar]
  33. Kamal-Eldin, A.; Appelqvist, L.A. The chemistry and antioxidant properties of tocopherols and tocotrienols. Lipids 1996, 31, 671–701. [Google Scholar]
  34. Cillard, J.; Cillard, P. Prooxidant effect of alpha-tocopherol on essential fatty acids in aqueous media. Ann. Nutr. Aliment. 1980, 34, 579–591. [Google Scholar]
  35. Burton, G.W.; Traber, M.G. Vitamin E: Antioxidant activity, biokinetics, and bioavailability. Annu. Rev. Nutr. 1990, 10, 357–382. [Google Scholar] [PubMed]
  36. Burton, G.W.; Ingold, K.U. Vitamin E as an in vitro and in vivo antioxidant. Ann. N. Y. Acad. Sci. 1989, 570, 7–22. [Google Scholar] [PubMed]
  37. Lee, I.M.; Cook, N.R.; Gaziano, J.M.; Gordon, D.; Ridker, P.M.; Manson, J.E.; Hennekens, C.H.; Buring, J.E. Vitamin E in the primary prevention of cardiovascular disease and cancer: The Women’s Health Study: A randomized controlled trial. J. Am. Med. Assoc. 2005, 294, 56–65. [Google Scholar]
  38. Hensley, K.; Benaksas, E.J.; Bolli, R.; Comp, P.; Grammas, P.; Hamdheydari, L.; Mou, S.; Pye, Q.N.; Stoddard, M.F.; Wallis, G.; et al. New perspectives on vitamin E: Gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine. Free Radic. Biol. Med. 2004, 36, 1–15. [Google Scholar] [PubMed]
  39. Kline, K.; Lawson, K.A.; Yu, W.; Sanders, B.G. Vitamin E and breast cancer prevention: Current status and future potential. J. Mammary Gland Biol. Neoplasia 2003, 8, 91–102. [Google Scholar]
  40. Bairati, I.; Meyer, F.; Gelinas, M.; Fortin, A.; Nabid, A.; Brochet, F.; Mercier, J.P.; Tetu, B.; Harel, F.; Masse, B.; et al. A randomized trial of antioxidant vitamins to prevent second primary cancers in head and neck cancer patients. J. Natl. Cancer Inst. 2005, 97, 481–488. [Google Scholar] [CrossRef] [PubMed]
  41. Brigelius-Flohe, R.; Kelly, F.J.; Salonen, J.T.; Neuzil, J.; Zingg, J.M.; Azzi, A. The European perspective on vitamin E: Current knowledge and future research. Am. J. Clin. Nutr. 2002, 76, 703–716. [Google Scholar]
  42. Li, G.X.; Lee, M.J.; Liu, A.B.; Yang, Z.; Lin, Y.; Shih, W.J.; Yang, C.S. delta-tocopherol is more active than alpha- or gamma-tocopherol in inhibiting lung tumorigenesis in vivo. Cancer Prev. Res. (Phila.) 2011, 4, 404–413. [Google Scholar] [CrossRef] [PubMed]
  43. Barve, A.; Khor, T.O.; Nair, S.; Reuhl, K.; Suh, N.; Reddy, B.; Newmark, H.; Kong, A.N. Gamma-tocopherol-enriched mixed tocopherol diet inhibits prostate carcinogenesis in TRAMP mice. Int. J. Cancer 2009, 124, 1693–1699. [Google Scholar]
  44. American Cancer Society. Learn about Cancer-Breast Cancer, 2011. Available online: (accessed on 25 May 2011).
  45. Blows, F.M.; Driver, K.E.; Schmidt, M.K.; Broeks, A.; van Leeuwen, F.E.; Wesseling, J.; Cheang, M.C.; Gelmon, K.; Nielsen, T.O.; Blomqvist, C.; et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: A collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010, 7, e1000279. [Google Scholar] [PubMed]
  46. Sorlie, T.; Tibshirani, R.; Parker, J.; Hastie, T.; Marron, J.S.; Nobel, A.; Deng, S.; Johnsen, H.; Pesich, R.; Geisler, S.; et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc. Natl. Acad. Sci. USA 2003, 100, 8418–8423. [Google Scholar]
  47. Russo, J.; Hasan Lareef, M.; Balogh, G.; Guo, S.; Russo, I.H. Estrogen and its metabolites are carcinogenic agents in human breast epithelial cells. J. Steroid Biochem. Mol. Biol. 2003, 87, 1–25. [Google Scholar]
  48. Mense, S.M.; Remotti, F.; Bhan, A.; Singh, B.; El-Tamer, M.; Hei, T.K.; Bhat, H.K. Estrogen-induced breast cancer: Alterations in breast morphology and oxidative stress as a function of estrogen exposure. Toxicol. Appl. Pharmacol. 2008, 232, 78–85. [Google Scholar]
  49. Singh, B.; Mense, S.M.; Remotti, F.; Liu, X.; Bhat, H.K. Antioxidant butylated hydroxyanisole inhibits estrogen-induced breast carcinogenesis in female ACI rats. J. Biochem. Mol. Toxicol. 2009, 23, 202–211. [Google Scholar]
  50. Yager, J.D.; Davidson, N.E. Estrogen carcinogenesis in breast cancer. N. Engl. J. Med. 2006, 354, 270–282. [Google Scholar]
  51. Gaikwad, N.W.; Rogan, E.G.; Cavalieri, E.L. Evidence from ESI-MS for NQO1-catalyzed reduction of estrogen ortho-quinones. Free Radic. Biol. Med. 2007, 43, 1289–1298. [Google Scholar]
  52. Sumi, D.; Numasawa, Y.; Endo, A.; Iwamoto, N.; Kumagai, Y. Catechol estrogens mediated activation of Nrf2 through covalent modification of its quinone metabolite to Keap1. J. Toxicol. Sci. 2009, 34, 627–635. [Google Scholar]
  53. Rogan, E.G.; Badawi, A.F.; Devanesan, P.D.; Meza, J.L.; Edney, J.A.; West, W.W.; Higginbotham, S.M.; Cavalieri, E.L. Relative imbalances in estrogen metabolism and conjugation in breast tissue of women with carcinoma: Potential biomarkers of susceptibility to cancer. Carcinogenesis 2003, 24, 697–702. [Google Scholar]
  54. Owens, M.A.; Horten, B.C.; da Silva, M.M. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin. Breast Cancer 2004, 5, 63–69. [Google Scholar] [CrossRef] [PubMed]
  55. Baselga, J.; Swain, S.M. Novel anticancer targets: Revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer 2009, 9, 463–475. [Google Scholar]
  56. Franklin, M.C.; Carey, K.D.; Vajdos, F.F.; Leahy, D.J.; de Vos, A.M.; Sliwkowski, M.X. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 2004, 5, 317–328. [Google Scholar]
  57. Lewis Phillips, G.D.; Li, G.; Dugger, D.L.; Crocker, L.M.; Parsons, K.L.; Mai, E.; Blattler, W.A.; Lambert, J.M.; Chari, R.V.; Lutz, R.J.; et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res. 2008, 68, 9280–9290. [Google Scholar] [PubMed]
  58. Spector, N.L.; Xia, W.; Burris, H., III; Hurwitz, H.; Dees, E.C.; Dowlati, A.; O’Neil, B.; Overmoyer, B.; Marcom, P.K.; Blackwell, K.L.; et al. Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J. Clin. Oncol. 2005, 23, 2502–2512. [Google Scholar] [PubMed]
  59. Citri, A.; Alroy, I.; Lavi, S.; Rubin, C.; Xu, W.; Grammatikakis, N.; Patterson, C.; Neckers, L.; Fry, D.W.; Yarden, Y. Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: Implications for cancer therapy. EMBO J. 2002, 21, 2407–2417. [Google Scholar]
  60. Hynes, N.E.; Lane, H.A. ERBB receptors and cancer: The complexity of targeted inhibitors. Nat. Rev. Cancer 2005, 5, 341–354. [Google Scholar]
  61. Olayioye, M.A.; Neve, R.M.; Lane, H.A.; Hynes, N.E. The ErbB signaling network: Receptor heterodimerization in development and cancer. EMBO J. 2000, 19, 3159–3167. [Google Scholar]
  62. Burgess, A.W.; Cho, H.S.; Eigenbrot, C.; Ferguson, K.M.; Garrett, T.P.; Leahy, D.J.; Lemmon, M.A.; Sliwkowski, M.X.; Ward, C.W.; Yokoyama, S. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol. Cell 2003, 12, 541–552. [Google Scholar]
  63. Tzahar, E.; Waterman, H.; Chen, X.; Levkowitz, G.; Karunagaran, D.; Lavi, S.; Ratzkin, B.J.; Yarden, Y. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol. Cell Biol. 1996, 16, 5276–5287. [Google Scholar]
  64. Pinkas-Kramarski, R.; Soussan, L.; Waterman, H.; Levkowitz, G.; Alroy, I.; Klapper, L.; Lavi, S.; Seger, R.; Ratzkin, B.J.; Sela, M.; Yarden, Y. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J. 1996, 15, 2452–2467. [Google Scholar]
  65. 65. Holbro, T.; Beerli, R.R.; Maurer, F.; Koziczak, M.; Barbas, C.F., III; Hynes, N.E. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc. Natl. Acad. Sci. USA 2003, 100, 8933-8938.
  66. Yarden, Y.; Sliwkowski, M.X. Untangling the ErbB signalling network. Nat. Rev. Mol. Cell Biol. 2001, 2, 127–137. [Google Scholar]
  67. Hellyer, N.J.; Cheng, K.; Koland, J.G. ErbB3 (HER3) interaction with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem. J. 1998, 333, 757–763. [Google Scholar]
  68. Brenton, J.D.; Carey, L.A.; Ahmed, A.A.; Caldas, C. Molecular classification and molecular forecasting of breast cancer: Ready for clinical application? J. Clin. Oncol. 2005, 23, 7350–7360. [Google Scholar] [PubMed]
  69. Peppercorn, J.; Perou, C.M.; Carey, L.A. Molecular subtypes in breast cancer evaluation and management: Divide and conquer. Cancer Invest. 2008, 26, 1–10. [Google Scholar]
  70. Carey, L.A.; Perou, C.M.; Livasy, C.A.; Dressler, L.G.; Cowan, D.; Conway, K.; Karaca, G.; Troester, M.A.; Tse, C.K.; Edmiston, S.; et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. J. Am. Med. Assoc. 2006, 295, 2492–2502. [Google Scholar]
  71. Kline, K.; Lawson, K.A.; Yu, W.; Sanders, B.G. Vitamin E and cancer. Vitam. Horm. 2007, 76, 435–461. [Google Scholar]
  72. Stone, W.L.; Krishnan, K.; Campbell, S.E.; Qui, M.; Whaley, S.G.; Yang, H. Tocopherols and the treatment of colon cancer. Ann. N. Y. Acad. Sci. 2004, 1031, 223–233. [Google Scholar]
  73. Chamras, H.; Barsky, S.H.; Ardashian, A.; Navasartian, D.; Heber, D.; Glaspy, J.A. Novel interactions of vitamin E and estrogen in breast cancer. Nutr. Cancer 2005, 52, 43–48. [Google Scholar]
  74. Rice, S.; Whitehead, S.A. Phytoestrogens oestrogen synthesis and breast cancer. J. Steroid Biochem. Mol. Biol. 2008, 108, 186–195. [Google Scholar]
  75. Comitato, R.; Nesaretnam, K.; Leoni, G.; Ambra, R.; Canali, R.; Bolli, A.; Marino, M.; Virgili, F. A novel mechanism of natural vitamin E tocotrienol activity: Involvement of ERbeta signal transduction. Am. J. Physiol. Endocrinol. Metab. 2009, 297, E427–E437. [Google Scholar]
  76. Smolarek, A.K.; So, J.Y.; Thomas, P.E.; Lee, H.J.; Paul, S.; Dombrowski, A.; Wang, C.X.; Kong, A.N.T.; Reuhl, K.; Lee, M.J.; et al. Dietary Mixed Tocopherols Inhibit Cell Proliferation in Mammary Hyperplasia, Suppress the Expression of Inflammatory Markers, and Upregulate PPARy. In Proceedings of the 102nd Annual Meeting of the American Association for Cancer ResearchOrlando, FL, USA, 2-6 April 2011.
  77. Desvergne, B.; Wahli, W. Peroxisome proliferator-activated receptors: Nuclear control of metabolism. Endocr. Rev. 1999, 20, 649–688. [Google Scholar]
  78. Michalik, L.; Desvergne, B.; Wahli, W. Peroxisome-proliferator-activated receptors and cancers: Complex stories. Nat. Rev. Cancer 2004, 4, 61–70. [Google Scholar]
  79. Mansure, J.J.; Nassim, R.; Kassouf, W. Peroxisome proliferator-activated receptor gamma in bladder cancer: A promising therapeutic target. Cancer Biol. Ther. 2009, 8, 6–15. [Google Scholar]
  80. Jarrar, M.H.; Baranova, A. PPARgamma activation by thiazolidinediones (TZDs) may modulate breast carcinoma outcome: The importance of interplay with TGFbeta signalling. J. Cell Mol. Med. 2007, 11, 71–87. [Google Scholar]
  81. Campbell, S.E.; Musich, P.R.; Whaley, S.G.; Stimmel, J.B.; Leesnitzer, L.M.; Dessus-Babus, S.; Duffourc, M.; Stone, W.; Newman, R.A.; Yang, P.; et al. Gamma tocopherol upregulates the expression of 15-S-HETE and induces growth arrest through a PPAR gamma-dependent mechanism in PC-3 human prostate cancer cells. Nutr. Cancer 2009, 61, 649–662. [Google Scholar] [CrossRef] [PubMed]
  82. De Pascale, M.C.; Bassi, A.M.; Patrone, V.; Villacorta, L.; Azzi, A.; Zingg, J.M. Increased expression of transglutaminase-1 and PPARgamma after vitamin E treatment in human keratinocytes. Arch. Biochem. Biophys. 2006, 447, 97–106. [Google Scholar]
  83. Bonofiglio, D.; Gabriele, S.; Aquila, S.; Catalano, S.; Gentile, M.; Middea, E.; Giordano, F.; Ando, S. Estrogen receptor alpha binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor gamma signaling in breast cancer cells. Clin. Cancer Res. 2005, 11, 6139–6147. [Google Scholar]
  84. Saw, C.L.; Wu, Q.; Kong, A.N. Anti-cancer and potential chemopreventive actions of ginseng by activating Nrf2 (NFE2L2) anti-oxidative stress/anti-inflammatory pathways. Chin. Med. 2010, 5, 37. [Google Scholar] [CrossRef] [PubMed]
  85. Surh, Y.J. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer 2003, 3, 768–780. [Google Scholar]
  86. Frohlich, D.A.; McCabe, M.T.; Arnold, R.S.; Day, M.L. The role of Nrf2 in increased reactive oxygen species and DNA damage in prostate tumorigenesis. Oncogene 2008, 27, 4353–4362. [Google Scholar]
  87. Kwak, M.K.; Kensler, T.W. Targeting NRF2 signaling for cancer chemoprevention. Toxicol. Appl. Pharmacol. 2010, 244, 66–76. [Google Scholar]
  88. Khor, T.O.; Yu, S.; Kong, A.N. Dietary cancer chemopreventive agents-Targeting inflammation and Nrf2 signaling pathway. Planta Med. 2008, 74, 1540–1547. [Google Scholar]
  89. Chen, C.; Kong, A.N. Dietary cancer-chemopreventive compounds: From signaling and gene expression to pharmacological effects. Trends Pharmacol. Sci. 2005, 26, 318–326. [Google Scholar]
  90. Feng, Z.; Liu, Z.; Li, X.; Jia, H.; Sun, L.; Tian, C.; Jia, L.; Liu, J. alpha-Tocopherol is an effective Phase II enzyme inducer: Protective effects on acrolein-induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells. J. Nutr. Biochem 2010, 21, 1222–1231. [Google Scholar]
  91. Yu, S.; Khor, T.O.; Cheung, K.L.; Li, W.; Wu, T.Y.; Huang, Y.; Foster, B.A.; Kan, Y.W.; Kong, A.N. Nrf2 expression is regulated by epigenetic mechanisms in prostate cancer of TRAMP mice. PLoS One 2010, 5, e0008579. [Google Scholar]
  92. Smolarek, A.K.; So, J.Y.; Thomas, P.E.; Lee, H.J.; Paul, S.; Dombrowski, A.; Wang, C.X.; Saw, C.L.-L.; Khor, T.O.; Kong, A.N.T.; et al. Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia. 2011. Unpublished work. [Google Scholar]
  93. Kerr, J.F. History of the events leading to the formulation of the apoptosis concept. Toxicology 2002, 181-182, 471–474. [Google Scholar] [CrossRef] [PubMed]
  94. Kerr, J.F.; Wyllie, A.H.; Currie, A.R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 1972, 26, 239–257. [Google Scholar]
  95. Hacker, G. The morphology of apoptosis. Cell Tissue Res. 2000, 301, 5–17. [Google Scholar]
  96. Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol. 2007, 35, 495–516. [Google Scholar]
  97. Igney, F.H.; Krammer, P.H. Death and anti-death: Tumour resistance to apoptosis. Nat. Rev. Cancer 2002, 2, 277–288. [Google Scholar]
  98. Cohen, G.M. Caspases: The executioners of apoptosis. Biochem. J. 1997, 326, 1–16. [Google Scholar]
  99. Rai, N.K.; Tripathi, K.; Sharma, D.; Shukla, V.K. Apoptosis: A basic physiologic process in wound healing. Int. J. Low. Extrem. Wounds 2005, 4, 138–144. [Google Scholar]
  100. Campbell, S.E.; Stone, W.L.; Lee, S.; Whaley, S.; Yang, H.; Qui, M.; Goforth, P.; Sherman, D.; McHaffie, D.; Krishnan, K. Comparative effects of RRR-alpha- and RRR-gamma-tocopherol on proliferation and apoptosis in human colon cancer cell lines. BMC Cancer 2006, 6, 13. [Google Scholar] [CrossRef] [PubMed]
  101. Jiang, Q.; Wong, J.; Ames, B.N. Gamma-tocopherol induces apoptosis in androgen-responsive LNCaP prostate cancer cells via caspase-dependent and independent mechanisms. Ann. N. Y. Acad. Sci. 2004, 1031, 399–400. [Google Scholar]
  102. Yu, W.; Simmons-Menchaca, M.; Gapor, A.; Sanders, B.G.; Kline, K. Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols. Nutr. Cancer 1999, 33, 26–32. [Google Scholar]
  103. Yu, W.; Jia, L.; Wang, P.; Lawson, K.A.; Simmons-Menchaca, M.; Park, S.K.; Sun, L.; Sanders, B.G.; Kline, K. In vitro and in vivo evaluation of anticancer actions of natural and synthetic vitamin E forms. Mol. Nutr. Food Res. 2008, 52, 447–456. [Google Scholar] [CrossRef] [PubMed]
  104. Suh, N.; Paul, S.; Lee, H.J.; Ji, Y.; Lee, M.J.; Yang, C.S.; Reddy, B.S.; Newmark, H.L. Mixed tocopherols inhibit N-methyl-N-nitrosourea-induced mammary tumor growth in rats. Nutr. Cancer 2007, 59, 76–81. [Google Scholar] [CrossRef] [PubMed]
  105. Smolarek, A.K.; So, J.Y.; Kong, A.N.; Reuhl, K.; Lin, Y.; Shih, W.J.; Lee, M.J.; Yang, C.S.; Suh, N. Dietary administration of gamma- and delta-tocopherol inhibits mammary carcinogenesis. In Proceedings of Society of Toxicology’s 51st Annual Meeting & ToxExpo, San Francisco, CA, USA, 11-15 March 2012.
  106. Herschman, H.R. Prostaglandin synthase 2. Biochim. Biophys. Acta 1996, 1299, 125–140. [Google Scholar]
  107. Howe, L.R.; Subbaramaiah, K.; Brown, A.M.; Dannenberg, A.J. Cyclooxygenase-2: A target for the prevention and treatment of breast cancer. Endocr. Relat. Cancer 2001, 8, 97–114. [Google Scholar]
  108. Ristimaki, A.; Sivula, A.; Lundin, J.; Lundin, M.; Salminen, T.; Haglund, C.; Joensuu, H.; Isola, J. Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res. 2002, 62, 632–635. [Google Scholar]
  109. Howe, L.R.; Subbaramaiah, K.; Patel, J.; Masferrer, J.L.; Deora, A.; Hudis, C.; Thaler, H.T.; Muller, W.J.; Du, B.; Brown, A.M.; et al. Celecoxib, a selective cyclooxygenase 2 inhibitor, protects against human epidermal growth factor receptor 2 (HER-2)/neu-induced breast cancer. Cancer Res. 2002, 62, 5405–5407. [Google Scholar] [PubMed]
  110. Wagner, K.H.; Kamal-Eldin, A.; Elmadfa, I. Gamma-tocopherol-An underestimated vitamin? Ann. Nutr. Metab. 2004, 48, 169–188. [Google Scholar]
  111. Jiang, Q.; Yin, X.; Lill, M.A.; Danielson, M.L.; Freiser, H.; Huang, J. Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenase. Proc. Natl. Acad. Sci. USA 2008, 105, 20464–20469. [Google Scholar]
  112. Ambrosone, C.B.; Marshall, J.R.; Vena, J.E.; Laughlin, R.; Graham, S.; Nemoto, T.; Freudenheim, J.L. Interaction of family history of breast cancer and dietary antioxidants with breast cancer risk (New York, United States). Cancer Causes Control 1995, 6, 407–415. [Google Scholar]
  113. Ray, G.; Husain, S.A. Role of lipids, lipoproteins and vitamins in women with breast cancer. Clin. Biochem. 2001, 34, 71–76. [Google Scholar]
  114. Mannisto, S.; Pietinen, P.; Virtanen, M.; Kataja, V.; Uusitupa, M. Diet and the risk of breast cancer in a case-control study: Does the threat of disease have an influence on recall bias? J. Clin. Epidemiol. 1999, 52, 429–439. [Google Scholar]
  115. Ronco, A.; De Stefani, E.; Boffetta, P.; Deneo-Pellegrini, H.; Mendilaharsu, M.; Leborgne, F. Vegetables, fruits, and related nutrients and risk of breast cancer: A case-control study in Urugua. Nutr. Cancer 1999, 35, 111–119. [Google Scholar]
  116. Braga, C.; La Vecchia, C.; Negri, E.; Franceschi, S.; Parpinel, M. Intake of selected foods and nutrients and breast cancer risk: An age- and menopause-specific analysis. Nutr. Cancer 1997, 28, 258–263. [Google Scholar]
  117. Freudenheim, J.L.; Marshall, J.R.; Vena, J.E.; Laughlin, R.; Brasure, J.R.; Swanson, M.K.; Nemoto, T.; Graham, S. Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrient. J. Natl. Cancer Inst. 1996, 88, 340–348. [Google Scholar]
  118. London, S.J.; Stein, E.A.; Henderson, I.C.; Stampfer, M.J.; Wood, W.C.; Remine, S.; Dmochowski, J.R.; Robert, N.J.; Willett, W.C. Carotenoids, retinol, and vitamin E and risk of proliferative benign breast disease and breast cance. Cancer Causes Control 1992, 3, 503–512. [Google Scholar]
  119. Sharhar, S.; Normah, H.; Fatimah, A.; Fadilah, R.N.; Rohi, G.A.; Amin, I.; Cham, B.G.; Rizal, R.M.; Fairulnizal, M.N. Antioxidant intake and status, and oxidative stress in relation to breast cancer risk: A case-control study. Asian Pac. J. Cancer Prev. 2008, 9, 343–349. [Google Scholar]
  120. Levi, F.; Pasche, C.; Lucchini, F.; La Vecchia, C. Dietary intake of selected micronutrients and breast-cancer risk. Int. J. Cancer 2001, 91, 260–263. [Google Scholar]
  121. Negri, E.; La Vecchia, C.; Franceschi, S.; D’Avanzo, B.; Talamini, R.; Parpinel, M.; Ferraroni, M.; Filiberti, R.; Montella, M.; Falcini, F.; Conti, E.; Decarli, A. Intake of selected micronutrients and the risk of breast cancer. Int. J. Cancer 1996, 65, 140–144. [Google Scholar]
  122. Dorjgochoo, T.; Shrubsole, M.J.; Shu, X.O.; Lu, W.; Ruan, Z.; Zheng, Y.; Cai, H.; Dai, Q.; Gu, K.; Gao, Y.T.; et al. Vitamin supplement use and risk for breast cancer: The Shanghai Breast Cancer Study. Breast Cancer Res. Treat. 2008, 111, 269–278. [Google Scholar] [PubMed]
  123. Adzersen, K.H.; Jess, P.; Freivogel, K.W.; Gerhard, I.; Bastert, G. Raw and cooked vegetables, fruits, selected micronutrients, and breast cancer risk: A case-control study in Germa. Nutr. Cancer 2003, 46, 131–137. [Google Scholar]
  124. Zaroukian, S.; Pineault, R.; Gandini, S.; Lacroix, A.; Ghadirian, P. Correlation between nutritional biomarkers and breast cancer: A case-control study. Breast 2005, 14, 209–223. [Google Scholar]
  125. Tamimi, R.M.; Hankinson, S.E.; Campos, H.; Spiegelman, D.; Zhang, S.; Colditz, G.A.; Willett, W.C.; Hunter, D.J. Plasma carotenoids, retinol, and tocopherols and risk of breast cance. Am. J. Epidemiol. 2005, 161, 153–160. [Google Scholar]
  126. Sato, R.; Helzlsouer, K.J.; Alberg, A.J.; Hoffman, S.C.; Norkus, E.P.; Comstock, G.W. Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cance. Cancer Epidemiol. Biomark. Prev. 2002, 11, 451–457. [Google Scholar]
  127. Comstock, G.W.; Burke, A.E.; Hoffman, S.C.; Norkus, E.P.; Gross, M.; Helzlsouer, K.J. The repeatability of serum carotenoid, retinoid, and tocopherol concentrations in specimens of blood collected 15 years apar. Cancer Epidemiol. Biomark. Prev. 2001, 10, 65–68. [Google Scholar]
  128. Yang, Y.J.; Hwang, S.H.; Kim, H.J.; Nam, S.J.; Kong, G.; Kim, M.K. Dietary intake of nitrate relative to antioxidant vitamin in relation to breast cancer risk: A case-control study. Nutr. Cancer 2010, 62, 555–566. [Google Scholar]
  129. Simon, M.S.; Djuric, Z.; Dunn, B.; Stephens, D.; Lababidi, S.; Heilbrun, L.K. An evaluation of plasma antioxidant levels and the risk of breast cancer: A pilot case control study. Breast J. 2000, 6, 388–395. [Google Scholar]
  130. Bohlke, K.; Spiegelman, D.; Trichopoulou, A.; Katsouyanni, K.; Trichopoulos, D. Vitamins A, C and E and the risk of breast cancer: Results from a case-control study in Greece. Br. J. Cancer 1999, 79, 23–29. [Google Scholar]
  131. Mezzetti, M.; La Vecchia, C.; Decarli, A.; Boyle, P.; Talamini, R.; Franceschi, S. Population attributable risk for breast cancer: Diet, nutrition, and physical exercis. J. Natl. Cancer Inst. 1998, 90, 389–394. [Google Scholar]
  132. Dorgan, J.F.; Sowell, A.; Swanson, C.A.; Potischman, N.; Miller, R.; Schussler, N.; Stephenson, H.E., Jr. Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: Results from a prospective study in Columbia, Missouri (United Sta. Cancer Causes Control 1998, 9, 89–97. [Google Scholar]
  133. Wang, C.; Baumgartner, R.N.; Yang, D.; Slattery, M.L.; Murtaugh, M.A.; Byers, T.; Hines, L.M.; Giuliano, A.R.; Baumgartner, K.B. No evidence of association between breast cancer risk and dietary carotenoids, retinols, vitamin C and tocopherols in Southwestern Hispanic and non-Hispanic White wome. Breast Cancer Res. Treat 2009, 114, 137–145. [Google Scholar]
  134. Nissen, S.B.; Tjonneland, A.; Stripp, C.; Olsen, A.; Christensen, J.; Overvad, K.; Dragsted, L.O.; Thomsen, B. Intake of vitamins A, C, and E from diet and supplements and breast cancer in postmenopausal wome. Cancer Causes Control 2003, 14, 695–704. [Google Scholar]
  135. Do, M.H.; Lee, S.S.; Jung, P.J.; Lee, M.H. Intake of dietary fat and vitamin in relation to breast cancer risk in Korean women: A case-control study. J. Korean Med. Sci. 2003, 18, 534–540. [Google Scholar]
  136. Rohan, T.E.; Howe, G.R.; Friedenreich, C.M.; Jain, M.; Miller, A.B. Dietary fiber, vitamins A, C, and E, and risk of breast cancer: A cohort st. Cancer Causes Control 1993, 4, 29–37. [Google Scholar]
  137. Michels, K.B.; Holmberg, L.; Bergkvist, L.; Ljung, H.; Bruce, A.; Wolk, A. Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish wome. Int. J. Cancer 2001, 91, 563–567. [Google Scholar]
  138. Zhang, S.; Hunter, D.J.; Forman, M.R.; Rosner, B.A.; Speizer, F.E.; Colditz, G.A.; Manson, J.E.; Hankinson, S.E.; Willett, W.C. Dietary carotenoids and vitamins A, C, and E and risk of breast cance. J. Natl. Cancer Inst. 1999, 91, 547–556. [Google Scholar]
  139. Verhoeven, D.T.; Assen, N.; Goldbohm, R.A.; Dorant, E.; van’t Veer, P.; Sturmans, F.; Hermus, R.J.; van den Brandt, P.A. Vitamins C and E, retinol, beta-carotene and dietary fibre in relation to breast cancer risk: A prospective cohort stud. Br. J. Cancer 1997, 75, 149–155. [Google Scholar]
  140. Jarvinen, R.; Knekt, P.; Seppanen, R.; Teppo, L. Diet and breast cancer risk in a cohort of Finnish women. Cancer Lett. 1997, 114, 251–253. [Google Scholar]
  141. Kushi, L.H.; Fee, R.M.; Sellers, T.A.; Zheng, W.; Folsom, A.R. Intake of vitamins A, C, and E and postmenopausal breast cancer. The Iowa Women’s Health Study. Am. J. Epidemiol. 1996, 144, 165–174. [Google Scholar] [PubMed]
  142. Hunter, D.J.; Manson, J.E.; Colditz, G.A.; Stampfer, M.J.; Rosner, B.; Hennekens, C.H.; Speizer, F.E.; Willett, W.C. A prospective study of the intake of vitamins C, E, and A and the risk of breast cance. N. Engl. J. Med. 1993, 329, 234–240. [Google Scholar]
  143. Friedenreich, C.M.; Howe, G.R.; Miller, A.B. Recall bias in the association of micronutrient intake and breast cancer. J. Clin. Epidemiol. 1993, 46, 1009–1017. [Google Scholar]
  144. Graham, S.; Zielezny, M.; Marshall, J.; Priore, R.; Freudenheim, J.; Brasure, J.; Haughey, B.; Nasca, P.; Zdeb, M. Diet in the epidemiology of postmenopausal breast cancer in the New York State Cohort. Am. J. Epidemiol. 1992, 136, 1327–1337. [Google Scholar]
  145. Nagel, G.; Linseisen, J.; van Gils, C.H.; Peeters, P.H.; Boutron-Ruault, M.C.; Clavel-Chapelon, F.; Romieu, I.; Tjonneland, A.; Olsen, A.; Roswall, N.; et al. Dietary beta-carotene, vitamin C and E intake and breast cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Breast Cancer Res. Treat. 2010, 119, 753–765. [Google Scholar] [PubMed]
  146. Cui, Y.; Shikany, J.M.; Liu, S.; Shagufta, Y.; Rohan, T.E. Selected antioxidants and risk of hormone receptor-defined invasive breast cancers among postmenopausal women in the Women’s Health Initiative Observational Study. Am. J. Clin. Nutr. 2008, 87, 1009–1018. [Google Scholar]
  147. Cho, E.; Spiegelman, D.; Hunter, D.J.; Chen, W.Y.; Zhang, S.M.; Colditz, G.A.; Willett, W.C. Premenopausal intakes of vitamins A, C, and E, folate, and carotenoids, and risk of breast ca. Cancer Epidemiol. Biomark. Prev. 2003, 12, 713–720. [Google Scholar]
  148. Nechuta, S.; Lu, W.; Chen, Z.; Zheng, Y.; Gu, K.; Cai, H.; Zheng, W.; Shu, X.O. Vitamin supplement use during breast cancer treatment and survival: A prospective cohort study. Cancer Epidemiol. Biomark. Prev. 2011, 20, 262–271. [Google Scholar]
  149. Schwenke, D.C. Does lack of tocopherols and tocotrienols put women at increased risk of breast cancer? J. Nutr. Biochem 2002, 13, 2–20. [Google Scholar]
  150. Kimmick, G.G.; Bell, R.A.; Bostick, R.M. Vitamin E and breast cancer: A review. Nutr. Cancer 1997, 27, 109–117. [Google Scholar]
  151. Fulan, H.; Changxing, J.; Baina, W.Y.; Wencui, Z.; Chunqing, L.; Fan, W.; Dandan, L.; Dianjun, S.; Tong, W.; Da, P.; et al. Retinol, vitamins A, C, and E and breast cancer risk: A meta-analysis and meta-regression. Cancer Causes Control 2011, 22, 1383–1396. [Google Scholar] [CrossRef] [PubMed]
  152. The alpha-tocopherol, beta-carotene lung cancer prevention study: Design, methods, participant characteristics, and compliance. The ATBC Cancer Prevention Study Group. Ann. Epidemiol. 1994, 4, 1–10. [CrossRef] [PubMed]
  153. Albanes, D.; Malila, N.; Taylor, P.R.; Huttunen, J.K.; Virtamo, J.; Edwards, B.K.; Rautalahti, M.; Hartman, A.M.; Barrett, M.J.; Pietinen, P.; et al. Effects of supplemental alpha-tocopherol and beta-carotene on colorectal cancer: Results from a controlled trial (Finland). Cancer Causes Control 2000, 11, 197–205. [Google Scholar] [CrossRef] [PubMed]
  154. Heinonen, O.P.; Albanes, D.; Virtamo, J.; Taylor, P.R.; Huttunen, J.K.; Hartman, A.M.; Haapakoski, J.; Malila, N.; Rautalahti, M.; Ripatti, S.; et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: Incidence and mortality in a controlled trial. J. Natl. Cancer Inst. 1998, 90, 440–446. [Google Scholar] [CrossRef] [PubMed]
  155. Gaziano, J.M.; Glynn, R.J.; Christen, W.G.; Kurth, T.; Belanger, C.; MacFadyen, J.; Bubes, V.; Manson, J.E.; Sesso, H.D.; Buring, J.E. Vitamins E and C in the prevention of prostate and total cancer in men: The Physicians’ Health Study II randomized controlled trial. J. Am. Med. Assoc. 2009, 301, 52–62. [Google Scholar]
  156. Lippman, S.M.; Klein, E.A.; Goodman, P.J.; Lucia, M.S.; Thompson, I.M.; Ford, L.G.; Parnes, H.L.; Minasian, L.M.; Gaziano, J.M.; Hartline, J.A.; et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: The Selenium and Vitamin E Cancer Prevention Trial (SELECT). J. Am. Med. Assoc. 2009, 301, 39–51. [Google Scholar]
  157. Lonn, E.; Bosch, J.; Yusuf, S.; Sheridan, P.; Pogue, J.; Arnold, J.M.; Ross, C.; Arnold, A.; Sleight, P.; Probstfield, J.; et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: A randomized controlled trial. J. Am. Med. Assoc. 2005, 293, 1338–1347. [Google Scholar]
  158. Lin, J.; Cook, N.R.; Albert, C.; Zaharris, E.; Gaziano, J.M.; Van Denburgh, M.; Buring, J.E.; Manson, J.E. Vitamins C and E and beta carotene supplementation and cancer risk: A randomized controlled trial. J. Natl. Cancer Inst. 2009, 101, 14–23. [Google Scholar]
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