Novel Tumor Suppressive Mechanisms of Estrogen Receptor β in Prostate Cancer



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Estrogen receptor β (ERβ) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells, and endothelium of the blood vessels. Genomic deletion of ERβ led to hyperplasia of prostate epithelium as well as upregulation of androgen receptor (AR) regulated genes. ERβ has been shown to inhibit proliferation and induce apoptosis in prostate cancer cells; however, role of ERβ in regulating AR activity in prostate cancer has not been studied in detail. Additionally, the role of ERβ in PI3K/Akt/PTEN pathway, which is one of the most altered in prostate cancer, is not known. Chapter 2 of this dissertation describes the role of ERβ in regulating PI3K/Akt/PTEN pathway. ERβ upregulated INPP4B in prostate cancer cells, PC3, as well as non-malignant cells BPH-1. Upregulation of INPP4B inhibited Akt activity measured by phosphorylation of Ser473 and its downstream target GSK3β. Further, we show that ERβ inhibited migration of PC3 cells by upregulating INPP4B in wound healing assays. This regulation may indicate a role for ERβ in metastasis suppression. Androgen receptor is the main driver of primary as well as metastatic prostate cancer. Chapter 3 describes the role of ERβ in regulating AR expression and activity in prostate cancer cells LNCaP. Using global transcriptomic analysis of ERβ- expressing LNCaP cells, we found AR-signaling is the most downregulated effect after ERβ activation. We validated this regulation independently by transcript and protein measurement of established AR target genes FKBP5, CaMKK2, TBC1D4, as well as by luciferase reporter assay. We further demonstrated that downregulation of CaMKK2 inhibits activity of AMPK, a major energy sensing mechanism in cells. Taken together, these findings support tumor suppressive effects of ERβ in prostate cancer through novel mechanisms and indicate possibilities for therapeutic intervention.



Estrogen receptor β (ERβ), PI3K, Akt, Androgen receptor (AR), Prostate, cancer, INPP4B