Androgen Receptor Signaling Regulates DNA Repair in Prostate Cancers

Abstract

We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy (ADT) synergizes with ionizing radiation (IR). Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output which correlates with expression of a set of DNA repair genes. Employing RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with IR plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical non-homologous end joining.

Genome-wide analysis of AR binding and comparison with transcript expression in primary human fetal prostate fibroblasts and cancer associated fibroblasts

“…The majority of these studies have been conducted on prostate cancer cell lines and considerable effort has been made in defining AR targets in tumour epithelium [12][13][14][15][16][17]. This has revealed a transcriptional role for AR in tumour cells regulating cell proliferation, metabolism, survival and DNA repair [18,19]. Prostate cancer cell lines have also been used to determine the changes in AR transcriptional networks in both a hormonenaïve-and castrate-resistant setting and numerous studies have revealed distinct binding profiles in the androgen-independent setting [13,17,18,20,21].…”

ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

“…It was reported recently that DNA damage caused by ionizing radiation leads to the activation of AR, which in turn induces the expression of DNA repair genes that promote the survival of irradiated prostate cancer cells (47,48). Based on these reports, we expected that AR-inactivation would down regulate DDR signaling pathways and block the repair of damaged telomeres.…”

Imaging and Pathology Correlations for Different Risk Stratification Models for Intermediate-risk Prostate Cancer

“…Men with >50% cores positive, perineural invasion, or cT2b-c disease had a superior 5-year biochemical control of 96% when treated with a brachytherapy boost compared to 87% when treated with dose-escalated external beam radiotherapy alone. As ADT also improves outcomes in patients that tend to have larger tumors (unfavorable risk patients), ADT may in fact also be acting as an alternative way to dose escalate -by sensitizing cancer cells to radiation (21).…”