3.1. Dietary Amelioration of Inflammation Associated with Breast Cancer
Many studies suggest that low-grade inflammation is mitigated by healthy dietary habits, such as polyphenols and the Mediterranean food pattern, resulting in lower circulating concentrations of inflammatory markers [
17]. Western-type or meat-based patterns are positively associated with low-grade inflammation [
18]. Among the components of a healthy diet, whole grains, vegetables and fruits, and fish are all associated with lower inflammation, and a limited number of observational studies suggested a pro-inflammatory action of diets rich in saturated fatty acids or trans-monounsaturated fats [
19]. The association between inflammation and cancer has been reported elsewhere [
20], citing major mediators nuclear factor kappa B (NF-κB), tumour necrosis factor (TNF), and cyclooxygenase-2 (COX-2), given the combined role in inflammation, cell proliferation, angiogenesis, and metastasis. Inhibition of COX-2 thus blocking the inhibition cascade may be an important mechanism by which polyphenols exert benefit to the breast cancer patient. The consumption of polyphenol-rich foods is thought to have an effect in modulating low-grade inflammation [
21].
The inflammatory environment that promotes breast cancer tumour growth links to obesity and metabolic syndrome. Women who gain weight in adulthood and overweight postmenopausal women have a greater risk for breast cancer than lean women [
22]. However, there are inconsistencies regarding the effect modification of menopausal status. In contrast, evidence exists showing that overweight and obesity is associated with reduced risk in premenopausal women [
23]. Metabolic syndrome (clinically defined as having three of the following factors: Abdominal obesity, hypertension, hyperglycemia, high triglycerides, or low HDL cholesterol [
24] has been associated with a 2.6 times higher risk of breast cancer in postmenopausal women [
25]. It can be deduced that a range of factors, including age, hormone levels, and obesity and overweight, affect breast cancer risk. Because overweight and obesity are powerful modifiable risk factors [
26], interventions, including dietary intervention, should be investigated further. Whilst clear evidence links metabolic syndrome with increased risk of breast cancer, it is also clear that post-diagnosis weight gain occurs in 50%–95% of patients and is associated with poor prognosis. Excess weight gain is associated with elevated inflammatory markers, against which polyphenols may protect.
According to a study conducted on rats, dietary supplementation of a high-fat diet and polyphenols led to dramatic changes in gut microbial community structure [
27]. Cranberry polyphenols protected mice on a high-fat, high-sucrose diet against oxidative stress, inflammation, weight gain, and markers of metabolic syndrome [
28]. Chronic low-grade inflammation promoted by an individual’s diet and their functioning gut microbiota may influence cancer progression.
Dietary polyphenols may protect against breast cancer progression, despite limited absorption and digestion, raising questions about their mechanism of action. As discussed, polyphenols appear to alter gut microbiota in rats and mice and has also been demonstrated in human studies. It was found that a moderate intake of red wine had positive effects on the composition of the gut microbiota and a reduction in the inflammatory markers [
29]. Polyphenols may assist the breast cancer patient by minimizing weight gain, improving the inflammatory profile and altering gut microbiota activity, thus reducing tumour growth.
3.2. Antioxidant Action of Polyphenolics
Polyphenols are secondary metabolites of plants and are generally involved in defense against ultraviolet radiation or aggression due to their physiological effects and structure [
30]. Many of the biological actions of polyphenols have been attributed to their antioxidant properties; however, recent research has suggested that polyphenols may affect several cellular pathways, thereby exerting a pleiotropic effect [
31]. Cellular pathways initiated by polyphenols may delay and reduce the carcinogenic processes in breast tissue [
32,
33]. Oxidative stress is known to alter the cellular redox status, resulting in altered gene expression by the activation of several redox-sensitive transcription factors. This signaling cascade affects both cell growth and cell death. An increased rate of reactive oxygen species (ROS) production occurs in highly proliferative cancer cells, owing to oncogenic mutations that promote aberrant metabolism. The ability of dietary polyphenols to modulate cellular signal transduction pathways, through the activation or repression of multiple redox-sensitive transcription factors, has been claimed for their potential therapeutic use as chemo-preventive agents [
34].
Red wine polyphenols reduce breast cancer cell proliferation in a dose-dependent manner by specifically targeting steroid receptors and modifying the production of ROS [
4]. However, it should be noted that it would not be prudent to advise the breast cancer patient to consume alcohol, given the potentially damaging effects. Phenolic phytochemicals have a strong antioxidant potential due to the hydroxyl groups associated with their aromatic rings. Phenolic phytochemicals have been shown to increase the levels of anti-inflammatory genes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), and heme oxygenase (HO)-1 via activation of the transcription factor nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2). Thus, polyphenols have an inherent capacity to reduce ROS and other free radicals, thereby preventing their activation of oxidative stress and inflammation [
35]. Polyphenols are effective free radical scavengers and their antioxidant properties should not be overlooked. In a recent meta-analysis of data from 7500 participants, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes [
36]. Polyphenols where found to be protective against chronic disease, implying a change in oxidative status. The antioxidant properties of polyphenols are thought to delay and to fight the carcinogenic processes in breast tissue [
32,
33]. Further studies will likely provide additional insights into the mechanism of redox control of breast cancer. Whilst polyphenols appear to reduce oxidative stress, the degree to which breast cancer prognosis is improved is unclear.
3.3. Polyphenols Protect DNA from the Carcinogen-Induced Damage
Chronic activation of inflammatory processes is widely regarded as an enabling characteristic towards the development of cancer. We know that chronic inflammation can drive tumour growth and the production of ROS [
37]. In turn, ROS can cause DNA damage. Production of ROS, together with deficiencies in the capacity to repair DNA (genotype dependent), can interact to increase carcinogenic capabilities [
37,
38]. Base-excision repair genes, such as
XRCC1 G399A [
37] and
OGG1 C326G, are associated with reduced repair of DNA lesions associated with ROS [
39].
The mutagen sensitivity assay (MSA) can be used as a marker of the ability of DNA to respond to and repair DNA damage and hence it has been used to test response to mutagens and bioactives [
38]. The Comet and Micronucleus assays have also been extensively used to determine the extent of DNA strand breaks and repair [
40,
41,
42], and there are a number of other methods, including RAD1 focus formation [
43], PCR, and the TUNEL assay, as well as numerous others [
44].
Germline mutations in DNA mismatch repair genes (
BRCA1,
BRCA2,
CHEK2,
ERCC4,
FAAP100, and
TP53BP1, amongst others) are associated with breast cancer susceptibility [
45,
46]. In some cases, it may be possible to modify diet to help decrease the risk of breast cancer and breast cancer recurrence [
45]. In a study of triple negative breast cancer (TNBC) patients, Lee et al. assessed 16 single nucleotide polymorphisms (SNPs) associated with DNA repair [
45]. The authors found that the risk of TNBC was associated with six of the SNPs and that this risk was modified by zinc, folate, and β-carotene levels such that low levels increased risk [
45]. These effects were additive. In other studies, it has been reported that high plasma levels of β-carotene, or the consumption of a carotenoid rich diet, were associated with lower levels of breast cancer or breast cancer recurrence [
10,
11] or a reduction in oxidative stress in those previously treated for breast cancer [
47]. Others found that diets rich in fruits and salads, a food pattern traditionally high in polyphenols, was associated with a reduced risk of breast cancer, particularly estrogen and progesterone receptor negative breast cancers [
12].
Polyphenols can act as pro- and anti-oxidants, depending on the experimental or environmental conditions [
41], and may modify the interaction between carcinogenic capabilities and breast cancer risk. In addition, polyphenols may enhance repair or change methylation status of promoter regions to favour DNA repair, or protect against DNA damage. Adams et al. found that polyphenols from blueberries inhibited cell proliferation and cell migration in human TNBC cell lines [
48] and decreased tumour size and inhibited metastasis in a TNBC xenograft study in mice [
49]. Similarly, Meeran et al. assessed the effect of Epigallocatechin-3-gallate (EGCG) and sulforaphane, an isothiocynate derived predominantly from plants of the order Brassicales and known to have strong chemo-preventative and anti-inflammatory properties on breast cancer cell lines [
50,
51]. They found that sulforaphane and EGCG inhibited cell proliferation, telomerase activity, and
human telomerase reverse transcriptase (
hTERT) gene expression [
50,
51].
hTERT is widely expressed in cancers, but not in normal cells, and downregulation of
hTERT in breast cancer can lead to the inhibition of cell proliferation and the induction of apoptosis. Food or dietary compound induced changes in
hTERT expression, which, in many cases, are due to epigenetic modifications [
50,
51,
52].
3.5. Polyphenol-Rich Dietary Pattern and Breast Cancer Progression
The Mediterranean diet has been shown to reduce body weight by 4.4% over a year and improve the inflammatory profile in cardiac and diabetic groups. Given the tendency for breast cancer survivors to gain weight and risk metabolic syndrome, the Mediterranean diet may assist with weight loss and provide specific benefits over and above the usual low-fat, healthy diet intervention. The Mediterranean diet is a plant-based dietary pattern characterized by a high intake of olive oil, legumes, whole grains, fruit, vegetables, nuts, seeds, fish, and is rich in dietary polyphenols. The diet has been linked to a decreased risk of developing breast cancer [
48]. The Mediterranean diet contains a wide range of various polyphenols, particularly from nuts, fruit, and coffee [
68], and represents a potential population approach to increasing the intake of polyphenols. Epidemiological evidence strongly suggests that long-term consumption of diets rich in plant polyphenols, much like that of the Mediterranean diet, can offer protection against development of major chronic and neurodegenerative diseases [
69,
70]. Suggested mechanisms through which the Mediterranean diet may impact breast cancer initiation and proliferation include increased insulin sensitivity and reduction of excess insulin production, anti-inflammatory and antioxidant effects of the diet, high fibre content, and an association with reduced risk of excess weight gain and obesity [
48]. The health benefits of the Mediterranean diet are likely a synergistic effect of weight loss, polyphenol intake, and improved glycemic control.
There are three main randomised trials investigating the effect of following a Mediterranean diet pattern and the prognosis following treatment for breast cancer. The results, however, are mixed. In 2007, The Women’s Healthy Eating and Living (WHEL) Randomised Trial found that a diet high in vegetable, fruit, and fibre and low in fat intake did not reduce additional breast cancer events or mortality over a relatively long follow-up period [
13]. These results are at odds with the Women’s Intervention Nutrition Study (WINS), a randomised trial that focused on a low-fat diet and weight loss, reporting that this diet was associated with longer relapse-free survival of breast cancer patients [
71]. Follow up times and differences in menopausal status between studies may explain outcomes. Difficulties in ascertaining the polyphenol content of these diets make conclusions regarding efficacy difficult.
Another reason for the difference in the results of these trials may be that, in WINS, the women lost weight in the randomised group, whereas those women in the WHEL study had an iso-caloric diet by design, and the women in the intervention group gained around 1 kg. The results from previous observational studies suggesting calorie reduction and weight loss are beneficial in breast cancer prognosis may add context to this situation and show why the results of the WHEL study were to no effect. Such an interpretation is verified by the relatively consistent observations that overweight and obese breast cancer patients have a worse prognosis than lean patients [
1,
72,
73,
74]. The Mediterranean diet has been shown to support weight loss in participants and as such may offer multiple benefits in polyphenol intake and weight loss.
The most recent randomised trial investigating the effects of a Mediterranean macrobiotic lifestyle on breast cancer prognosis is the DIANA-5 trial [
75]. It demonstrated that dietary modification based on Mediterranean and macrobiotic dietary principles can reduce body weight, and the bioavailability of sex hormones and growth factors may promote tumour growth [
76,
77]. The diet consisted of low consumption of fats, refined carbohydrates and animal products, and the high consumption of whole grain cereals, legumes, and vegetables.
Chemotherapy works to significantly decrease recurrences and improve survival in women with early breast cancer, but a major side effect is weight gain which, as discussed, is associated with a poorer prognosis [
78]. The trial showed this specific diet significantly decreases body weight and waist circumference, thereby improving insulin sensitivity [
79]. Like the WINS trial, only post-menopausal women were included in the study. The results may have differed for pre-menopausal women if they were also included.
Overall, the DIANA-5 trial has the potential to provide a clear answer to the hypothesis that a comprehensive modification of diet can lead to a longer event-free survival among women after breast cancer treatment [
75]. Intervention has been shown to be effective in changing lifestyle in terms of diet and weight loss. Combined with other modifiable factors, a Mediterranean diet that focuses on weight loss and reducing insulin resistance may have substantial benefits for women previously treated for breast cancer. All of these studies have pieced together components that warrant further investigation to the role of a Mediterranean-based diet and breast cancer prognosis, event-free survival, and mortality.
3.6. Disease Characteristics and Biomarkers
A reduction in breast cancer incidence and mortality is the gold standard criteria for success in a clinical trial; however, this approach is expensive and ethically difficult to implement. The use of surrogate breast cancer biomarkers is an appealing alternative. Breast cancer biomarkers useful for investigating the efficacy of polyphenols include specific oncogenic pathways (e.g., COX-2, or prostaglandin E2, a product of COX mediated catalysis), levels of circulating disease related proteins, such as ostrodial or estrogen, changes in breast cancer histology and cytology, genomic alterations
A major challenge in the treatment of breast cancer is its high heterogeneity from patient to patient, which initiated its classification into three major molecular subtypes—estrogen receptors (ER), progesterone receptors (PR), and HER2, hormone receptor positive with luminal A (ER+PR+HER2−) and luminal B (ER+PR+HER2+) phenotypes, HER2 positive (ER−PR−HER2+), and triple negative/basal-like (ER−PR−HER2−) [
80,
81,
82]. About 70% of breast cancers are estrogen receptor positive [
83]. Recent data suggest that molecular subtypes differ substantially in the intracellular pathways responsible for cell growth and metastatic spread, suggesting a wide array of potential molecular targets of polyphenols [
84]. The efficacy of polyphenolic therapy is likely to differ pending the breast cancer stage and subtype.
3.7. Epigenetic Potential of Polyphenolic Phytochemicals
Epigenetics refers to heritable changes in DNA that are involved in the control of gene expression. Epigenetic mechanisms include changes in DNA methylation, histone modification, and non-coding RNAs [
84]. While epigenetic characteristics are sometimes inherited they can also be modified by environmental and dietary factors. Inflammatory pathways can trigger epigenetic switches from nontransformed to metastatic cancer cells via signalling involving NF κB and STAT3 transcription factors, microRNAs (Lin28 and let-7), and IL-6 cytokines [
85]. Moreover, the polyphenols resveratrol and quercetin decreased miRNA-155 and inhibited NF-κB-involved inflammation in a cancer cell line study. Increasing evidence suggests polyphenols are capable of influencing epigenetic characteristics relevant to cancer progression. It is beyond the scope of this review to outline all the research of all aspects of the epigenetic potential of polyphenols; other reviews have been completed [
85]. Of the more notable epigenetic modification by polyphenols, epigenetically modified genes can be restored, inactivated methylated genes can be demethylated, and histone complexes can be rendered transcriptionally active by dietary intervention. Common to cancer initiation is the inhibition of tumour suppressor genes by DNA methylation of transcription factors. DNA methyltransferase (DNMT) inhibitors can undergo such methylation, which polyphenols have been demonstrated to reverse [
86].
Polyphenols can also alter heritable gene expression, activity of epigenetic machinery and decreases micro-RNAs related to inflammation and cancer growth. So far, it is not clear whether the occasional or typical dietary intake of polyphenols results in long-term epigenetic regulation of gene expression, downstream chemo-preventative effects, or both.
3.8. Bioavailability of Polyphenols
Biological properties of polyphenols depend on their bioavailability. The chemical structure of polyphenols determines their rate and extent of intestinal absorption, as well as the nature of the metabolites circulating in the plasma. For most flavonoids absorbed in the small intestine, the plasma concentration rapidly decreases (elimination half-life period of 1–2 h). The elimination half-life period for quercetin is much higher (24 h) probably due to its particularly high affinity for plasma albumin [
87]. Flavonols, isoflavones, flavones, and anthocyanins are usually glycosylated. Following high-dose polyphenol administration, metabolism occurs primarily in the liver, whereas, when smaller doses were administered, metabolism took place first at the intestinal mucosa, the liver playing a secondary role to further modify the conjugated polyphenol. This implies that the intestine is an important site for metabolism of food-derived polyphenols [
88]. Intestinal microbiological fermentation decreases the bioavailability of the many polyphenols; however, it also gives rise to metabolites that may be more bioactive than the native polyphenols [
88]. Metabolic responses based on dose also suggest that any potential benefit will vary based on the polyphenol dose used. Studies on ideal dose and delivery route are needed.
To circumvent poor bioavailability of polyphenols, a current area of promising research is using nanotechnology. One such nanotechnology, titled “Nano emulsions”, are a class of extremely small droplets that allow polyphenol phytochemicals to be transported through the cell membranes more easily, resulting in an increased concentration in plasma and improved bioavailability. Curcumin Nano emulsions show 85% inhibition of 12-
O-Tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear inflammation as well as the inhibition of cyclin D1 expression. In addition, dibenzoylmethane (DBM) Nano emulsions improve oral bioavailability of curcumin 3-fold, compared with the conventional DBM emulsions [
89]. The degree to which improved bioavailability improves survival in breast cancer patients is still to be determined, as there is likely a dose-response that is still to be ascertained.
3.9. Limitations (Toxicity, Bioavailability, Challenges and Weaknesses Associated with Human Trials, etc.)
Several factors have been proposed to explain differences observed between the positive effects of polyphenol consumption reported in epidemiological studies and the unclear to negative findings reported in intervention trials with supplements. These factors include the following: (1) differing doses of administered compounds; (2) additive or synergistic effects, such as those between polyphenols and other antioxidants, present in whole foods but not in supplements; and (3) differences in bioavailability and metabolism [
88]. Results from randomised clinical trials vary to those of in vitro studies largely as a result of these factors.
With any human dietary study, interpreting outcomes and defining appropriate dietary recommendations can be extremely difficult. Studies typically involve many methodological considerations such as dietary pattern differences across populations, accurately measuring food intake, biological mechanisms, genetic variations, food definitions, bias, and other confounding factors [
90]. Adding further complication is that many studies between cancer and diet provide weak associations, whereby confounding factors, exposure misclassification, and other biases, even modest ones, can have a large impact on the overall conclusions [
91]. To best answer questions regarding efficacy of dietary polyphenols, in vitro studies of polyphenol metabolites should be followed up with human clinical trials and we would recommend that further studies use placebo controlled, double-blind trials that extend over many years with a sufficient sample size. Unfortunately, such studies are expensive to conduct.