Estrogen receptor alpha drives proliferation in PTEN-deficient prostate carcinoma by stimulating survival signaling, MYC expression and altering glucose sensitivity

Abstract

While high doses of estrogen, in combination with androgens, can initiate prostate cancer (PCa) via activation of the estrogen receptor α (ERα), the role of ERα in PCa cells within established tumors is largely unknown. Here we show that expression of ERα is increased in high grade human PCa. Similarly, ERα is elevated in mouse models of aggressive PCa driven by MYC overexpression or deletion of PTEN. Within the prostate of PTEN-deficient mice, there is a progressive pattern of ERα expression: low in benign glands, moderate in tumors within the dorsal, lateral and ventral lobes, and high in tumors within the anterior prostate. This expression significantly correlates with the proliferation marker Ki67. Furthermore, in vitro knockdown of ERα in cells derived from PTEN-deficient tumors causes a significant and sustained decrease in proliferation. Depletion of ERα also reduces the activity of the PI3K and MAPK pathways, both downstream targets of non-genomic ERα action. Finally, ERα knockdown reduces the levels of the MYC protein and lowers the sensitivity of cellular proliferation to glucose withdrawal, which correlates with decreased expression of the glucose transporter GLUT1. Collectively, these results demonstrate that ERα orchestrates proliferation and metabolism to promote the neoplastic growth of PCa cells.

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

“…The most significant ERα gene expression, at mRNA and protein levels, was observed in hormone refractory tumours and metastatic lesions, including lymph node and bone metastases (Bonkhoff et al 1999). Furic and coworkers (Takizawa et al 2015) selected a cohort of tumours of Gleason grade 6 and 9 to ensure that both low-and high-grade tumours were represented; they found that ERα was expressed in 48% of Gleason score 9 specimens, but no ERα was observed in the Gleason score 6 tumours, thus confirming the earlier findings by Bonkhoff and coworkers. Another recent study reported that 15% of locally invasive tumours, spanning Gleason score 6-10, expressed ERα and that it was significantly associated with biochemical recurrence, decreased progression-free survival and poor overall survival (Takizawa et al 2015).…”

“…Furic and coworkers (Takizawa et al 2015) selected a cohort of tumours of Gleason grade 6 and 9 to ensure that both low-and high-grade tumours were represented; they found that ERα was expressed in 48% of Gleason score 9 specimens, but no ERα was observed in the Gleason score 6 tumours, thus confirming the earlier findings by Bonkhoff and coworkers. Another recent study reported that 15% of locally invasive tumours, spanning Gleason score 6-10, expressed ERα and that it was significantly associated with biochemical recurrence, decreased progression-free survival and poor overall survival (Takizawa et al 2015). A further study has reported that the expression of ERα and aromatase (CYP19) with the R264C polymorphism, a missense SNP located on the CYP19A1 locus, has been shown to result in shorter progression-free survival and an increased risk of developing CRPC in a study of 115 men treated with docetaxel.…”

“…Many studies report negligible ERα staining in prostate cancer cells using immunohistochemistry. This could be due to an underrepresentation of high-grade samples because other studies showed that ERα expression in prostate cancer cells is significantly associated with high Gleason score and poor patient survival (Takizawa et al 2015). Using immunohistochemical staining and in situ hybridisation studies of prostate cancer tissues, Bonkhoff and coworkers demonstrated the presence of ERα in both premalignant lesions and prostatic adenocarcinoma.…”

In touch with your feminine side: how oestrogen metabolism impacts prostate cancer

“…This further demonstrates that ERα regulates cell proliferation through PI3K and MAPK signalling (Takizawa et al 2015).…”

A Bright Future for Hormones and Cancer: Farewell Comments of Dr. Carol A. Lange, Recent Past Editor-in-Chief

“…Hormone receptor rapid actions and more recently receptor cross talk with other nuclear receptors (i.e., actions that require phosphorylation events) remain hot topics for HOCA content (i.e., estrogen and progesterone or androgen receptor cross talk in breast cancer). Participation of multiple steroid hormone receptors in the same signaling and transcriptional complexes [1,2] is likely a paradigm for many hormone-influenced cancers, such as prostate cancer (where ER-alpha may drive proliferation of advanced disease) [3] and even lung cancer, where progesterone receptor (PR) expression predicts poor outcome, while mineralocorticoid receptor (MR) expression appears to be protective [4].…”