Abstract
Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor β (ERβ) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ERβ agonist (8β-VE2) administration this treatment impairs regeneration, causing cystic atrophy that correlates with sustained depletion of p63+ basal cells. Furthermore, agonist treatment attenuates clonogenicity and self-renewal of murine prostatic stem/progenitor cells and depletes both murine (Lin−Sca1+CD49fhi) and human (CD49fhiTrop2hi) prostatic basal cells. Finally, we demonstrate the combined added benefits of selective stimulation of ERβ, including the induction of cell death in quiescent post-castration tissues. Subsequent to castration ERβ-induces further apoptosis in basal, luminal and intermediate cells. Our results reveal a novel benefit of ERβ activation for prostate disease and suggest that combining selective activation of ERβ with androgen-deprivation may be a feasible strategy to target stem cells implicated in the origin of prostatic disease.
Highlights
Androgen deprivation therapy (ADT) has been the standard of care for prostatic disease since 1941, when a landmark publication by Huggins and Hodges showed significant clinical benefit to prostate cancer patients treated with either surgical or chemical castration [1]
We showed that a single transient exposure to estrogen receptor b (ERb) agonist perturbed prostatic epithelial regeneration of the ventral prostate, 21 days later, even if androgen levels were supplemented by testosterone implants [8]
There are direct, local actions of estrogens on the prostate, mediated through both estrogen receptor subtypes and the development of estrogen selective modulators has distinguished between the adverse effects mediated through ERa and the beneficial ones mediated by ERb
Summary
Androgen deprivation therapy (ADT) has been the standard of care for prostatic disease since 1941, when a landmark publication by Huggins and Hodges showed significant clinical benefit to prostate cancer patients treated with either surgical or chemical castration [1]. In this setting, estrogens were administered to reduce hypothalamic pituitary stimulation of LH/FSH production and suppress androgen synthesis. ERb-induced apoptosis is mechanistically different, using the TNFa extrinsic apoptotic signaling pathway rather than the intrinsic pathway activated by castration Dependency on both ERb and TNFa was proven using siRNA and knockout mouse models [8]
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