Abstract
The estrogen signaling pathway has been reported to modulate prostate cancer (PCa) progression through the activity of estrogen receptors α and β (ERα and ERβ). Given that selective estrogen receptor modulators (SERMs) are used to treat breast cancer, ERs have been proposed as attractive therapeutic targets in PCa. However, many inconsistencies regarding the expression of ERs and the efficacy of SERMs for PCa treatment exist, notably due to the use of ERβ antibodies lacking specificity and treatments with high SERM concentrations leading to off-target effects. To end this confusion, our objective was to study the impact of estrogenic and anti-estrogenic ligands in well-studied in vitro PCa models with appropriate controls, dosages, and ER subtype-specific antibodies. When using physiologically relevant concentrations of nine estrogenic/anti-estrogenic compounds, including five SERMs, we observed no significant modulation of PCa cell proliferation. Using RNA-seq and validated antibodies, we demonstrate that these PCa models do not express ERs. In contrast, RNA-seq from PCa samples from patients have detectable expression of ERα. Overall, our study reveals that commonly used PCa models are inappropriate to study ERs and indicate that usage of alternative models is essential to properly assess the roles of the estrogen signaling pathway in PCa.
Highlights
In the context of prostate cancer (PCa), the androgen receptor (AR) has many oncogenic functions such as increasing the proliferation and survival of cancer cells[1]
Estrogens and the most active form estradiol (E2) are naturally produced from androgens through steroidogenesis and have been linked to PCa evolution, as reviewed recently by Dobbs et al.[8]. It has been demonstrated in murine models and in human patients that increased levels of estrogens were positively correlated with the aggressiveness of PCa9–15, and that estrogen synthesis increases in cancer cells during disease progression[16,17,18,19,20]
In the case of human AR-negative PCa cell lines (DU145 and PC3), they both showed no expression of AR and ERβ
Summary
In the context of prostate cancer (PCa), the androgen receptor (AR) has many oncogenic functions such as increasing the proliferation and survival of cancer cells[1]. The actual model supports that ERα has oncogenic functions, as seen in murine models where its activation leads to an increased proliferation of cancer cells[24,25,26]; on the other hand, ERβ is thought to act as a tumor suppressor since its loss promotes prostate hyperplasia and the development of the disease[21,27,28,29,30] Further supporting this model, ERα expression is reported to be increased and ERβ to be decreased during PCa progression[31,32,33,34,35,36,37]. The aim of our study was to perform a systematic investigation of the impact of treatments with natural estrogen, specific ERα and ERβ ligands, and SERMs, at specific concentrations, on PCa cell proliferation
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