The role of estrogen receptors in prostate cancer development and their role in new treatment opportunities

Abstract

The androgen receptor (AR) signaling pathway is one of the key pathways deregulated in prostate cancer (PCa). Different attempts to inhibit AR signaling failed to be curative. Therefore, the targeting of other pathways involved in PCa, such as the estrogen receptor (ER) pathways became a new field of research. The present study aimed to investigate how ER signaling regulates PCa development and growth and if ER β activation is a potential treatment opportunity for different stages of PCa. This study investigated the function of the two ERs, ER α and ER β, in PCa using TRAMP (transgenic adenocarcinoma of mouse prostate) mice and TRAMP mice with either an ER α knockout (ERKO) or an ER β knockout (BERKO). ERKO/TRAMP mice developed prostatic intraepithelial neoplastic lesions but no PCa which correlates with the previously described tumor promoting function of ER α. In contrast, both, TRAMP and BERKO/TRAMP, developed PCa with comparable incidence and malignancies. Cell lines generated from TRAMP and BERKO/TRAMP PCas showed similar proliferation rates. Here, the tumor suppressive effect of ER β described in the literautre could not be confirmed. To further investigate the role of ER β in PCa, cell lines depicting different PCa stages were treated with the ER β-specific agonist 8β-VE2. This treatment led to efficient cell survival reduction and induction of apoptosis in all PCa stages. 8β-VE2 treatment downregulated AR and AR splice variant expression and thereby reverses the adaptation to androgen deprivation therapy. However, we found that the observed effects of 8β-VE2 treatment on PCa cells were not solely ER β-mediated. More likely, the effects in 8β-VE2-treated PCa cells could be induced by the restoration of the full AR signaling, i.e. activation of AR gene transcription, for example by membrane-bound AR signaling, cofactor activation and the inhibition of an AR-regulated alternative survival pathway. 8β-VE2 was identified as an effective anti-cancerous drug, decreasing PCa cell survival, AR and ARV expression and inducing apoptosis. However, further studies are needed to elucidate the underlying molecular mechanism of action. Another aim of this study was to elucidate the role of the natural occurring cyanogenic diglucoside amygdalin in PCa. Cyanide was described to be the active component of amygdalin. Here, we investigated the effect of amygdalin on PCa growth in vivo. We observed a reduced incidence of metastasis formation under treatment with high amygdalin concentrations compared to control mice. Furthermore, high dose amygdalin increased the formation of necrotic tumor tissue. Analyses concerning the underlying mechanisms of amygdalin-induced effects were performed on murine primary PCa cell lines due to the massive induction of necrosis in the in vivo model. Amygdalin reduced the cell survival and invasiveness but without the induction of apoptosis or cytotoxic effects. Cell morphological changes and increased expression of senescence associated β-gal showed that senescence was induced in amygdalin-treated cell lines. Thus, for the first time the present study provides evidence-based indications for amygdalin’s anti-cancerous potential in PCa treatment in vivo.