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Estrogens in Human Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 16927

Special Issue Editors


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Guest Editor
Unit of Research & Internationalization (SIRS), ARNAS-Civico, Palermo, Italy
Interests: cancer biology; hormones & cancer; stem cells; nutrition & cancer; primary prevention; cell-to-cell communication; sex steroid metabolism; estrogens & chronic diseases; nuclear receptors; signal transduction
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Molecular Medicine Group, School of Biological Sciences, University of Reading, Reading, UK
Interests: aromatase; breast cancer; prostate cancer; EDCs; global health

Special Issue Information

Dear Colleagues,

Estrogens must be considered as a superfamily of pleiotropic regulators of development, structure, function and homeostatic control of a large array of human tissues, organs and systems. Estrogen superfamily is composed by both parent (circulating) hormones, precisely estradiol and estrone, and their metabolic derivatives that are brought about by the activity of metabolizing enzymes in target tissues.

Estrogens act through complex and multifaceted interactions that include either genomic or nongenomic, estrogen receptor (ER)-mediated or ER-independent mechanisms. Recent advances in the field have also revealed that estrogens may act through G protein-coupled estrogen receptors (GPER), a seven transmembrane receptor that activates nongenomic MAPK/ERK pathways upon estrogen binding.

Furthermore, ultimate estrogen activity in target tissues is determined by the expression, localization and activity of key enzymes, such as 17bhydroxysteroid-dehydrogenases, 2-, 4-, and 16-hydroxylases, catechol-O-methyltransferases, sulpho- and glucuronyl-transferases. These enzymes may produce bioactive or inert metabolites featured by either beneficial or toxic effects.

Although estrogens act as physiological regulators, their excess, deficiency and/or alteration of signaling machinery may eventually lead to developing a variety of human diseases, including cancer. In this framework, an integrated knowledge on estrogen signaling and metabolism appears to be essential not only for a deeper understanding of estrogen-related mechanisms underlying  various classical (e.g. breast, prostate) and nonclassical (e.g. colorectal, liver, lung) hormone-related tumors, but also to provide an important experimental basis for developing preventive strategies and/or targeted therapies of human cancers.

Prof. Dr. Giuseppe Carruba
Prof. Dr. Graeme Williams
Guest Editors

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Keywords

  • estrogen superfamily
  • estrogen metabolizing enzymes
  • estrogen receptor and GPER
  • genomic and nongenomic mechanisms
  • classical and nonclassical hormone-related tumors
  • environmental estrogens and cancer
  • estrogen-associated prevention and treatment of cancer

Published Papers (4 papers)

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Research

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10 pages, 18761 KiB  
Article
Less Carcinogenic Chlorinated Estrogens Applicable to Hormone Replacement Therapy
by Yoshinori Okamoto, Hideto Jinno, Shinji Itoh and Shinya Shibutani
Int. J. Mol. Sci. 2021, 22(13), 7222; https://doi.org/10.3390/ijms22137222 - 05 Jul 2021
Viewed by 1917
Abstract
Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE2) or 4-chloro-17β-estradiol (4-ClE2) was [...] Read more.
Human estrogens prescribed for hormone replacement therapy (HRT) are known to be potent carcinogens. To find safer estrogens, several chlorinated estrogens were synthesized and their carcinogenic potential were determined. A pellet containing either 2-chloro-17β-estradiol (2-ClE2) or 4-chloro-17β-estradiol (4-ClE2) was implanted subcutaneously for 52 weeks into August Copenhagen Irish (ACI) rats, a preferred animal model for human breast cancer. 17β-Estradiol (E2) frequently induced mammary tumors while both 2-ClE2 and 4-ClE2 did not. Their 17α-ethinyl forms, thought to be orally active estrogens, were also synthesized. Neither 2-chloro-17α-ethinylestradiol (2-ClEE2) nor 4-chloro-17α-ethinylestradiol (4-ClEE2) induced tumors. The less carcinogenic effects were supported by histological examination of mammary glands of ACI rats treated with the chlorinated estrogens. A chlorine atom positioned at the 2- or 4-position of E2 may prevent the metabolic activation, resulting in reducing the carcinogenicity. 2-ClE2 and 4-ClE2 administered subcutaneously and 2-ClEE2 and 4-ClEE2 given orally to ovariectomized rats all showed uterotrophic potency, albeit slightly weaker than that of E2. Our results indicate that less carcinogenic chlorinated estrogens retaining estrogenic potential could be safer alternatives to the carcinogenic estrogens now in use for HRT. Full article
(This article belongs to the Special Issue Estrogens in Human Cancer)
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10 pages, 2349 KiB  
Article
Heterogeneous Nuclear Ribonucleoprotein K Is Involved in the Estrogen-Signaling Pathway in Breast Cancer
by Erina Iwabuchi, Yasuhiro Miki, Takashi Suzuki, Hisashi Hirakawa, Takanori Ishida and Hironobu Sasano
Int. J. Mol. Sci. 2021, 22(5), 2581; https://doi.org/10.3390/ijms22052581 - 04 Mar 2021
Cited by 7 | Viewed by 2018
Abstract
Heterogeneous nuclear ribonucleoprotein K (hnRNPK) transcripts are abundant in estrogen receptor (ER)- or progesterone receptor (PR)-positive breast cancer. However, the biological functions of hnRNPK in the ER-mediated signaling pathway have remained largely unknown. Therefore, this study analyzes the functions of hnRNPK expression in [...] Read more.
Heterogeneous nuclear ribonucleoprotein K (hnRNPK) transcripts are abundant in estrogen receptor (ER)- or progesterone receptor (PR)-positive breast cancer. However, the biological functions of hnRNPK in the ER-mediated signaling pathway have remained largely unknown. Therefore, this study analyzes the functions of hnRNPK expression in the ER-mediated signaling pathway in breast cancer. We initially evaluated hnRNPK expression upon treatment with estradiol (E2) and ICI 182,780 in the ERα-positive breast carcinoma cell line MCF-7. The results revealed that E2 increased hnRNPK; however, hnRNPK expression was decreased with ICI 182,780 treatment, indicating estrogen dependency. We further evaluated the effects of hnRNPK knockdown in the ER-mediated signaling pathway in MCF-7 cells using small interfering RNAs. The results revealed that hnRNPK knockdown decreased ERα expression and ERα target gene pS2 by E2 treatment. As hnRNPK interacts with several other proteins, we explored the interaction between hnRNPK and ERα, which was demonstrated using immunoprecipitation and proximity ligation assay. Subsequently, we immunolocalized hnRNPK in patients with breast cancer, which revealed that hnRNPK immunoreactivity was significantly higher in ERα-positive carcinoma cells and significantly lower in Ki67-positive or proliferative carcinoma cells. These results indicated that hnRNPK directly interacted with ERα and was involved in the ER-mediated signaling pathway in breast carcinoma. Furthermore, hnRNPK expression could be an additional target of endocrine therapy in patients with ERα-positive breast cancer. Full article
(This article belongs to the Special Issue Estrogens in Human Cancer)
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Review

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40 pages, 2476 KiB  
Review
Exploring the Biological Activity and Mechanism of Xenoestrogens and Phytoestrogens in Cancers: Emerging Methods and Concepts
by Xiaoqiang Wang, Desiree Ha, Ryohei Yoshitake, Yin S. Chan, David Sadava and Shiuan Chen
Int. J. Mol. Sci. 2021, 22(16), 8798; https://doi.org/10.3390/ijms22168798 - 16 Aug 2021
Cited by 17 | Viewed by 7154
Abstract
Xenoestrogens and phytoestrogens are referred to as “foreign estrogens” that are produced outside of the human body and have been shown to exert estrogen-like activity. Xenoestrogens are synthetic industrial chemicals, whereas phytoestrogens are chemicals present in the plant. Considering that these environmental estrogen [...] Read more.
Xenoestrogens and phytoestrogens are referred to as “foreign estrogens” that are produced outside of the human body and have been shown to exert estrogen-like activity. Xenoestrogens are synthetic industrial chemicals, whereas phytoestrogens are chemicals present in the plant. Considering that these environmental estrogen mimics potentially promote hormone-related cancers, an understanding of how they interact with estrogenic pathways in human cells is crucial to resolve their possible impacts in cancer. Here, we conducted an extensive literature evaluation on the origins of these chemicals, emerging research techniques, updated molecular mechanisms, and ongoing clinical studies of estrogen mimics in human cancers. In this review, we describe new applications of patient-derived xenograft (PDX) models and single-cell RNA sequencing (scRNA-seq) techniques in shaping the current knowledge. At the molecular and cellular levels, we provide comprehensive and up-to-date insights into the mechanism of xenoestrogens and phytoestrogens in modulating the hallmarks of cancer. At the systemic level, we bring the emerging concept of window of susceptibility (WOS) into focus. WOS is the critical timing during the female lifespan that includes the prenatal, pubertal, pregnancy, and menopausal transition periods, during which the mammary glands are more sensitive to environmental exposures. Lastly, we reviewed 18 clinical trials on the application of phytoestrogens in the prevention or treatment of different cancers, conducted from 2002 to the present, and provide evidence-based perspectives on the clinical applications of phytoestrogens in cancers. Further research with carefully thought-through concepts and advanced methods on environmental estrogens will help to improve understanding for the identification of environmental influences, as well as provide novel mechanisms to guide the development of prevention and therapeutic approaches for human cancers. Full article
(This article belongs to the Special Issue Estrogens in Human Cancer)
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11 pages, 1620 KiB  
Review
The 3,4-Quinones of Estrone and Estradiol Are the Initiators of Cancer whereas Resveratrol and N-acetylcysteine Are the Preventers
by Ercole Cavalieri and Eleanor Rogan
Int. J. Mol. Sci. 2021, 22(15), 8238; https://doi.org/10.3390/ijms22158238 - 30 Jul 2021
Cited by 7 | Viewed by 4775
Abstract
This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react [...] Read more.
This article reviews evidence suggesting that a common mechanism of initiation leads to the development of many prevalent types of cancer. Endogenous estrogens, in the form of catechol estrogen-3,4-quinones, play a central role in this pathway of cancer initiation. The catechol estrogen-3,4-quinones react with specific purine bases in DNA to form depurinating estrogen-DNA adducts that generate apurinic sites. The apurinic sites can then lead to cancer-causing mutations. The process of cancer initiation has been demonstrated using results from test tube reactions, cultured mammalian cells, and human subjects. Increased amounts of estrogen-DNA adducts are found not only in people with several different types of cancer but also in women at high risk for breast cancer, indicating that the formation of adducts is on the pathway to cancer initiation. Two compounds, resveratrol, and N-acetylcysteine, are particularly good at preventing the formation of estrogen-DNA adducts in humans and are, thus, potential cancer-prevention compounds. Full article
(This article belongs to the Special Issue Estrogens in Human Cancer)
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