Abstract 5042: Dynamic transcriptional regulation of ERα targets in prostate cancer
Authors: Cotter Kellie , Chakravarty Dimple , Sboner Andrea , Rubin Mark A. 
Published: August 2015

Introduction: Prostate cancer is the second most common cause of cancer death in American men. Prostate cancer is mainly an androgen receptor regulated disease, however estrogen signaling is also important in prostate physiology and development particularly in aging men as decreasing testosterone is accompanied by increasing estrogen levels. Further, estrogen signaling through estrogen receptor alpha (ERα) has been implicated in prostate cancer progression, and ERα expression increases in high grade tumors, however its precise role remains unclear. Thus far there have been no systematic approaches to assay ERα transcriptional regulation in prostate cancer, and in this study we aim to determine the role of ERα in prostate cancer by identifying direct ERα target genes.

Methods: ERα recruitment profile was assayed by ChIP-Seq in both NCI-H660 and ERα overexpressing VCaP cells in response to estrogen treatment. ERα transcriptional regulation of target genes was examined utilizing RNA-Seq in VCaP cells with and without ERα overexpression. Candidate gene expression was assayed via qPCR in prostate cancer cell lines, and by RNA-Seq in a 126 sample prostate cancer patient cohort.

Results: In order to delineate the role of ERα in prostate cancer we integrated RNA- and ChIP-Seq datasets from two different cell lines in response to ERα overexpression and estrogen treatment. In doing so we identified an ERα signature comprising multiple genes that were significantly up or down-regulated (&gt; 5-fold) and had an ERα binding site near the gene promoter. Many of these ERα target genes have been previously identified as oncogenes or tumor suppressors, and they include members several key pathways including PI3 kinase signaling and cytoskeleton maintenance. Expression of these target genes was queried in multiple prostate cancer cell lines, and interestingly ERα binding sites and estrogen regulation were cell line specific in both androgen receptor positive and negative lines. Further, significant differences in target gene expression were demonstrated between benign prostate and prostate adenocarcinoma (PCa), and/or between PCa and castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). Combinatorial targeting of both ERα and PI3K signaling proved beneficial for prostate cancer.

Conclusion: These results demonstrate that estrogen regulates a distinct set of genes in prostate cancer in a direct genomic fashion, including several components of the PI3K pathway. They also support the hypothesis that this ERα signature is dynamic and changes during the course of prostate cancer progression to CRPC and NEPC. Further validation of the pathways involved is necessary, however these findings may lead to the discovery of novel co-targeting treatment strategies and/or prostate cancer biomarkers, and assessment of ERα signaling may help predict a subclass of prostate cancer patients that are likely to respond to PI3K inhibition.

Citation Format: Kellie Cotter, Dimple Chakravarty, Andrea Sboner, Mark A. Rubin. Dynamic transcriptional regulation of ERα targets in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5042. doi:10.1158/1538-7445.AM2015-5042