Dr. Weeks’ Comment: It is well known among doctors that estrogen is a proliferative (growth inducing) substance and that the World Health Organization (WHO) has listed estrogens as “carcinogenic to humans”. This is nuanced though and to call this dance of hormones a double-edged sword is too much of a simplification. However, the role of estrogens in prostate cancer deserves a closer analysis since presently, most oncologists fault exclusively testosterone as the agent which “throws fuel on the fire of cancer’. However, if testosterone, the androgenic male hormone, does indeed fuel prostate cancer, it begs the question of why prostate cancer only shows up when testosterone levels drop in men after 50 years old. Why wouldn’t men who are creating huge amounts of testosterone in their 20s and 30s get prostate cancer? Coupled with that question is the fact that testosterone degrades or metabolize into – the chemical term is ‘aromatizes into – estrogen itself. Many weightlifters discovered this when dosing with high amounts of testosterone for muscle building and discovered that they developed gynecomastia or male boobs. They were spiking with testosterone, but their estrogen levels rose. This is probably what happens with all men in their 60s, who have an increasingly a difficult time retaining testosterone, because it aromatizes into estrogen. Given the fact that estrogen is considered a carcinogen question is what role does estrogen have in prostate cancer?
Let’s review some recent peer reviewed scientific literature. Share this data with your oncologist.
RESEARCH to CONSIDER
J Clin Invest. 2024 Apr 16;134(11):e170809.
doi: 10.1172/JCI170809.
The estrogen signaling pathway reprograms prostate cancer cell metabolism and supports proliferation and disease progression
Camille Lafront 1 2 3, Lucas Germain 1 2 3, Gabriel H Campolina-Silva 4 5, Cindy Weidmann 2 3,
Abstract
Just like the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ERα functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen-targeted therapies for the treatment of this disease. Using 2 human PCa tissue microarray cohorts, we first demonstrate that nuclear ERα expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ERα levels were correlated with disease recurrence, progression to metastatic PCa, and patient survival. Using in vitro and in vivo models of the normal prostate and PCa, bulk and single-cell RNA-Seq analyses revealed that estrogens partially mimicked the androgen transcriptional response and activated specific biological pathways linked to proliferation and metabolism. Bioenergetic flux assays and metabolomics confirmed the regulation of cancer metabolism by estrogens, supporting proliferation. Using cancer cell lines and patient-derived organoids, selective estrogen receptor modulators, a pure anti-estrogen, and genetic approaches impaired cancer cell proliferation and growth in an ERα-dependent manner. Overall, our study revealed that, when expressed, ERα functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes.
~~~
Prostate Cancer Prostatic Dis. 2019 May;22(2):185-194.
doi: 10.1038/s41391-018-0081-6. Epub 2018 Aug 21.
Estrogens and prostate cancer
Ryan W Dobbs 1, et al
Abstract
Background: Hormonal influences such as androgens and estrogens are known contributors in the development and progression of prostate cancer (CaP). While much of the research to the hormonal nature of CaP has focused on androgens, estrogens also have critical roles in CaP development, physiology as well as a potential therapeutic intervention.
Methods: In this review, we provide a critical literature review of the current basic science and clinical evidence for the interaction between estrogens and CaP.
Results: Estrogenic influences in CaP include synthetic, endogenous, fungi and plant-derived compounds, and represent a family of sex hormones, which cross hydrophobic cell membranes and bind to membrane-associated receptors and estrogen receptors that localize to the nucleus triggering changes in gene expression in various organ systems.
Conclusions: Estrogens represent an under-recognized contributor in CaP development and progression. Further research in this topic may provide opportunities for identification of environmental influencers as well as providing novel therapeutic targets in the treatment of CaP.
~~~
J Clin Invest. 2024 Apr 16;134(11):e170809.
doi: 10.1172/JCI170809.
The estrogen signaling pathway reprograms prostate cancer cell metabolism and supports proliferation and disease progression
Camille Lafront 1 2 3, Lucas Germain 1 2 3, Gabriel H Campolina-Silva 4 5, Cindy Weidmann 2 3,
Abstract
Just like the androgen receptor (AR), the estrogen receptor α (ERα) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ERα functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen-targeted therapies for the treatment of this disease. Using 2 human PCa tissue microarray cohorts, we first demonstrate that nuclear ERα expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ERα levels were correlated with disease recurrence, progression to metastatic PCa, and patient survival. Using in vitro and in vivo models of the normal prostate and PCa, bulk and single-cell RNA-Seq analyses revealed that estrogens partially mimicked the androgen transcriptional response and activated specific biological pathways linked to proliferation and metabolism. Bioenergetic flux assays and metabolomics confirmed the regulation of cancer metabolism by estrogens, supporting proliferation. Using cancer cell lines and patient-derived organoids, selective estrogen receptor modulators, a pure anti-estrogen, and genetic approaches impaired cancer cell proliferation and growth in an ERα-dependent manner. Overall, our study revealed that, when expressed, ERα functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes.
~~~
J Endocr Soc. 2024 Jun 4;8(7):bvae107.
doi: 10.1210/jendso/bvae107. eCollection 2024 May 23.
The Loss of Estradiol by Androgen Deprivation in Prostate Cancer Patients Shows the Importance of Estrogens in Males
Herjan J T Coelingh Bennink 1, Amanda Prowse 2, Jan F M Egberts 2, Frans M J Debruyne 3, Ilpo T Huhtaniemi 4, Bertrand Tombal 5
Abstract
The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical consequences of E2 deficiency in men and discuss the effects of restoration of levels of this reproductive steroid hormone. In men with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT), E2 is suppressed along with testosterone, leading to side effects affecting the quality of life. These include hot flashes, arthralgia, fatigue, mood changes, cognition problems, weight gain, bone loss, and increased risk of cardiovascular disease. Transdermal E2 alone for ADT has shown equivalent testosterone suppression compared to gonadotropin-releasing hormone (GnRH) agonists while also preventing estrogen-deficiency side effects, including hot flashes and bone loss. Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public.
https://pubmed.ncbi.nlm.nih.gov/38883397/
~~~
J Steroid Biochem Mol Biol. 2024 Jul:241:106522.
doi: 10.1016/j.jsbmb.2024.106522. Epub 2024 Apr 17.
Androgen receptor and estrogen receptor variants in prostate and breast cancers
José C Valentín López 1, Carol A Lange 2, Scott M Dehm 3
Abstract
The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions. These inhibitors include competitive antagonists and degraders that directly bind the ligand binding domains of these receptors, luteinizing hormone releasing hormone (LHRH) analogs that suppress gonadal synthesis of testosterone or estrogen, and drugs that block specific enzymes required for biosynthesis of testosterone or estrogen. However, resistance to these therapies is frequent, and is often driven by selection for tumor cells with alterations in the AR or ESR1 genes and/or alternatively spliced AR or ESR1 mRNAs that encode variant forms AR or ERα. While most investigations involving AR have been within the context of prostate cancer, and the majority of investigations involving ERα have been within the context of breast cancer, important roles for AR have been elucidated in breast cancer, and important roles for ERα have been elucidated in prostate cancer. Here, we will discuss the roles of AR and ERα in breast and prostate cancers, outline the effects of gene- and mRNA-level alterations in AR and ESR1 on progression of these diseases, and identify strategies that are being developed to target these alterations therapeutically
https://pubmed.ncbi.nlm.nih.gov/38641298/
~~~
Review
Front Endocrinol (Lausanne). 2022 Jan 11:12:811578.
doi: 10.3389/fendo.2021.811578. eCollection 2021.
Distribution and Effects of Estrogen Receptors in Prostate Cancer: Associated Molecular Mechanisms
Adrián Ramírez-de-Arellano 1, Ana Laura Pereira-Suárez 1 2, Cecilia Rico-Fuentes 3, Edgar Iván López-Pulido 3, Julio César Villegas-Pineda 2, Erick Sierra-Diaz 4 5
Abstract
Estrogens are hormones that have been extensively presented in many types of cancer such as breast, uterus, colorectal, prostate, and others, due to dynamically integrated signaling cascades that coordinate cellular growth, differentiation, and death which can be potentially new therapeutic targets. Despite the historical use of estrogens in the pathogenesis of prostate cancer (PCa), their biological effect is not well known, nor their role in carcinogenesis or the mechanisms used to carry their therapeutic effects of neoplastic in prostate transformation. The expression and regulation of the estrogen receptors (ERs) ERα, ERβ, and GPER stimulated by agonists and antagonists, and related to prostate cancer cells are herein reviewed. Subsequently, the structures of the ERs and their splice variants, the binding of ligands to ERs, and the effect on PCa are provided. Finally, we also assessed the contribution of molecular simulation which can help us to search and predict potential estrogenic activities.
~~~