Prostate cancer (PCa) is the second leading cause of cancer-related deaths in males after lung cancer in the USA. Under normal conditions, the essential role of androgen through the androgen receptor (AR) is to support prostate epithelial cell growth, functional differentiation and survival. However, the androgen and AR-mediated signaling pathways can also promote genesis, progression and metastasis of prostate cancer. Thus, androgen deprivation or abrogation of the AR signaling remains the first-line treatment for human advanced prostate cancer. Unfortunately, these prostate cancers develop resistance to these therapies and progress to androgen-independent or castration-resistant prostate cancer (CRPC) with an average latency period of 18 months. Docetaxel chemotherapy and newly developed androgen synthesis blocker or AR signaling inhibitors have been demonstrated to be efficacious against CRPC. However, the median increase in survival was only four to five months. Thus, identification of molecular targets contributing to the initiation and progression of CRPC is a critical step to develop effective mechanism-based prostate cancer therapies. Recent studies provided compelling genetic evidence that Pten deletion, the most frequent genetic alterations identified in 70% of human advanced prostate cancers, promotes PCa progression to CRPC in preclinical mouse models. To understand the molecular mechanisms underlying Pten deletion-driven CRPC, we established an AR-positive prostate cancer cell line derived from an aggressive prostate tumor developed in a genetic mouse model carrying deletion of Pten only in prostate epithelium. Our initial characterization studies show that these cancer cells proliferated and grew well in an anchorage-independent growth assay either in the absence of androgen or genetic depletion of AR in vitro. In support of this notion, we found that these cancer cells formed tumors in female NOD/SCID IL2RG null mice. Interestingly, the tumors grow faster and larger in female NOD/SCID IL2RG null mice than in their male counterparts. These observations promoted us to further examine the role of estrogen in the development of CRPC. Genetic and pharmacologic studies suggested that estrogen, through its receptor alpha (ERα)-FOXA1-mediated signaling pathway, increased cancer cell proliferation in vitro and promoted prostate tumor development in xenografts in female SCID mice. Furthermore, we found that these cancer cells display features of epithelial-mesenchymal transition (EMT) as characterized by the loss of E-cadherin and CK8 coupled with an increase in N-cadherin, vimentin, and twist expression. Collectively, our data suggest that (ERα)-FOXA1-mediated signaling pathway and EMT play an important role in Pten deficiency-driven CRPC. Thus, targeting these signaling pathways might be a novel approach to complement current therapies of CRPC.

Citation Format: Fengxia Wu, Lei Wang, Hua Xiong, Li-Ju Chang, Tao Lin, Junxuan Lu, Yibin Deng. Role of estrogen and epithelial-mesenchymal-transition in Pten deletion-driven castration-resistant prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3028. doi:10.1158/1538-7445.AM2013-3028

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.