The Evolving Role Of Oestrogens And Their Receptors In The Development And Progression Of Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology;  Endocrinology
Article Date: 15 Dec 2008 - 0:00 PDT

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UroToday.com - The androgen receptor (AR) is currently the major target for prostate cancer (PCa) prevention and treatment. Nevertheless, there are multiple lines of evidence to suggest that oestrogens and their receptors are also involved in PCa development and tumor progression.

Oestrogens can affect normal and abnormal growth in the human prostate through at least two mechanisms:

-- Systemic (endocrine) effects by acting via the pituitary gland to indirectly lower serum androgen levels

-- Local effects that directly target the prostate by specific oestrogen receptors (ER), which may be present in epithelial (autocrine action) and stromal compartments (paracrine action) of prostate and PCa tissue.

The human prostate is equipped with a dual system of oestrogen receptors (ERa, ERb) that undergo profound remodeling during PCa development and tumor progression. The current data obtained from human tissue and animal models implicate the ERa as an oncogene, which is upregulated during PCa development (HGPIN) and tumor progression. Interestingly, the major ligand of the ERa derives from testosterone. The conversion of testosterone to estradiol is mediated by the P450 aromatase enzyme (CYP19 gene), which is active in adipose tissue, adrenal glands, testicules, and even the prostate. Therefore, aromatase may be a key regulator of the ratio of androgen to oestrogen in the prostate gland. The ERa antagonist toremifene prevents PCa and slow tumor progression in the TRAMP mouse model, and has been proven effective in reducing PCa detection in a phase 2 clinical trail enrolling 514 patients with diagnosed HGPIN.

In apparent contrast to ERa, the ERb, by binding phytoestrogens with high affinity, is considered a functional tumor suppressor, which is partially lost during PCa development (HGPIN) and castration resistant disease. The anticancer properties of phytoestrogens have been documented in vitro and in vivo, including inhibition of cell proliferation and angiogenesis, decrease of 5α- reductase activity and androgen receptor expression (AR silencing). Importantly, both oestrogen receptors (ERa, ERb) have been reported to regulate a potentially aggressive molecular subtype of prostate cancer, i.e. the TMPRSS2- ERG fusion.

Nevertheless, the translation of the current information into potential therapeutic applications remains highly challenging. A major problem is still agonist (= oestrogenic) effects of ERa antagonists. With the selective ER modulators (SERMs) currently available, it is perhaps unrealistic to expect objective clinical response in patients with end- stage hormone refractory disease. The usefulness of SERMs in hormone naïve prostate cancer in preventing disease progression has not yet been addressed by clinical studies. Little is known about the expression and function of ERb splice variants, ERa and ERb isoforms, ligand- dependent and ligand-independent activities, the role of genomic versus non-genomic signaling and the role of ER coactivators in regulating antagonist/ agonist response. Answers to these questions will further our understanding of ER signaling pathways and will open new avenues for drugs designed to antagonize ERa activity and function as ERβ agonists. This approach may provide new preventive and therapeutic strategies for prostate cancer.

Written by Helmut Bonkhoff, MD as part of Beyond the Abstract on UroToday.com

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