Antiproliferative and pro-apoptotic actions of Estrogen receptor β in prostate cancer
Dey, Prasenjit 1978-
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High Gleason grade prostate cancers are aggressive. Currently, the major target for treatment is the androgen receptor. Recent literature points towards a tumor suppressive role of estrogen receptor β (ERβ), which has a potential to be exploited as a target for novel therapeutics used for treatment of prostate cancer. In Chapter 2 of the thesis, we showed that ERβ-selective agonists elicited an increase in apoptosis and this was accompanied by an increase in expression of the pro-apoptotic factor PUMA. Induction of PUMA was dependent on the presence of the transcription factor FOXO3 but was independent of p53. In the ventral prostates of ERβ-/- mice, expression of FOXO3a is lower than that in WT littermates demonstrating a relationship between ERβ and FOXO3a expression found in PC3 and LNCaP cells. Furthermore, in prostate cancers of Gleason grade 4 or higher there was a marked reduction of both ERβ and FOXO3a, while both genes were well expressed in BPH sections. In Chapter 3 of the thesis, we investigated whether the loss of ERβ (also called as ERβ1) and/or expression of its splice variant ERβ2 affected signaling pathways involved in proliferation and bone metastasis of prostate cancer. We found repressed expression of the bone metastasis regulator Runx2 and its target gene, Slug by ERβ1. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade prostate cancer, was increased by ERβ2. In terms of cell cycle modification, of the two receptors, ERβ1, but not ERβ2, inhibited proliferation and expression of the proliferation markers Cyclin E, c-Myc, and p45Skp2. Xenograft studies using athymic nude mice confirmed the proliferative effect of ERβ2, as tumors in mice bearing PC3-ERβ2 cells were substantially larger than tumors in mice bearing PC3-control and PC3-ERβ1 cells.