The overarching question to be addressed in this proposal is how loss of estrogen receptor ? (ER?) function in tumor cells contributes to prostate cancer. The expression of ER? is diminished in prostate cancer, especially in aggressive, high Gleason grade tumors and its loss contributes to a de-differentiated, EMT phenotype. Importantly, loss of ER? increases expression of Bmi-1, a Polycomb group transcriptional repressor that functions as an oncoprotein and has been implicated in the self-renewal of prostate tumor stem cells. A key issue that arises from these findings is how loss of ER? contributes to Bmi-1 expression and the putative regulation of tumor initiating cells. ER? stabilizes HIF-1??and promotes HIF-1-mediated transcription but the mechanism involved in this critical process has not been resolved. This mechanism is extremely important and relevant because high-grade tumors exhibit significantly elevated expression of HIF-1??but clinically relevant hypoxia is not seen in localized primary prostate cancer including high-grade tumors. These observations indicate that loss of ER? in prostate cancer mimics hypoxia by stabilizing HIF-1?. It is proposed that ER? is necessary for the expression of specific prolyl hydroxylases that target HIF-1??for degradation, providing a potential mechanism for how loss of ER? induces HIF-1?, and that a major consequence of this mechanism is enhanced VEGF transcription and VEGF-mediated induction of Bmi-1. Collectively, this application will address the novel and exciting hypothesis that ER? impedes the acquisition of an EMT process that expands the population of tumor initiating cells and enhances their self-renewal, and that the progression of prostate cancer can be diminished by sustaining ER? function. To validate this hypothesis, two specific aims are proposed.
The first aim will determine that ligand-dependent activation of ER? promotes the proteosomal degradation of HIF-1??by sustaining the transcription of prolyl hydroxylase 2 (PHD2), and that loss of ER? expression or function diminishes PHD2 expression resulting in HIF-1??stabilization and HIF-1 activation that promotes a de-differentiated, EMT phenotype.
The second aim will establish that ER? signaling suppresses the HIF-1-mediated transcription of VEGF, which functions in an autocrine manner to sustain the expression of Bmi-1, promote an EMT and contribute to the function of prostate tumor initiating cells. Thus, it will be determined that loss of ER? and PHD2 contribute to tumorigenesis and aggressive disease by promoting an EMT and increasing the frequency of tumor initiating cells.

Public Health Relevance

This proposal seeks to understand why some prostate carcinomas are much more aggressive and offer a worse prognosis than others. The major goal of this proposal is to understand how loss of a specific form of the estrogen receptor causes prostate tumors to be more aggressive. To accomplish this goal, we will establish inhibits the genesis of cells that are capable of initiating tumors and making tumors more aggressive.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Woodhouse, Elizabeth
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University of Massachusetts Medical School Worcester
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Goel, Hira Lal; Pursell, Bryan; Shultz, Leonard D et al. (2016) P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer. Cell Rep 14:2193-2208
Mak, Paul; Li, Jiarong; Samanta, Sanjoy et al. (2015) Prostate tumorigenesis induced by PTEN deletion involves estrogen receptor ? repression. Cell Rep 10:1982-91
Mak, Paul; Li, Jiarong; Samanta, Sanjoy et al. (2015) ER? regulation of NF-kB activation in prostate cancer is mediated by HIF-1. Oncotarget 6:40247-54
Goel, Hira Lal; Gritsko, Tatiana; Pursell, Bryan et al. (2014) Regulated splicing of the ?6 integrin cytoplasmic domain determines the fate of breast cancer stem cells. Cell Rep 7:747-61
Mak, Paul; Chang, Cheng; Pursell, Bryan et al. (2013) Estrogen receptor ? sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription. Proc Natl Acad Sci U S A 110:4708-13
Goel, Hira Lal; Mercurio, Arthur M (2013) VEGF targets the tumour cell. Nat Rev Cancer 13:871-82