Abstract 2156: c-Myb promotes growth, invasion and androgen-independence of prostate cancer cells

Abstract

Abstract Most prostate cancer (PCa) patients treated with first line androgen-deprivation therapy (ADT) initially exhibit a dramatic regression of the androgen-dependent (AD) cancer cells; however, the tumors eventually progress to an androgen-independent (AI) stage. The resulting hormone-refractory tumors are highly aggressive and resistant to conventional therapies. The causal mechanisms for such a transition remain largely unknown; however, a number of genetic and epigenetic alterations are believed to be involved in the process of AI progression of PCa. In an earlier study, c-Myb was identified among the genes that are amplified at higher frequency in hormone-refractory PCa. The c-Myb proto-oncogene is a cellular progenitor of v-Myb oncogenes, which encodes for a transcription factor and confers its oncogenic activity by regulating the expression of several target genes. In the present study, we have investigated the functional role of c-Myb in prostate cancer cells. Our data showed that c-Myb was overexpressed in AI (C4-2) PCa cells as compared to AD (LNCaP) PCa cells of the same genotypic lineage. Furthermore, we found that c-Myb was regulated by androgens in a biphasic manner and its expression correlated with the effect of androgens on prostate cancer cell growth. Short-hairpin RNA (shRNA)-mediated silencing of c-Myb in C4-2 cells reduced their growth, clonogenicity, motility and invasion, whereas its ectopic expression in LNCaP cells had opposite effects. Moreover, we observed that the overexpression of c-Myb in LNCaP and C4-2 cells was associated with their growth in androgen-depleted media, suggesting its role in androgen-independence. Immunoblot analysis demonstrated loss of mesenchymal markers N-cadherin, vimentin, Slug, Snail, and Twist, and gain of epithelial marker, E-cadherin in c-Myb-silenced C4-2 cells. In contrast, c-Myb overexpressing LNCaP cells exhibited a loss of epithelial and gain of mesenchymal markers, thus indicating a role of c-Myb in epithelial to mesenchymal transition (EMT) of PCa cells. Altogether, our studies provide first experimental evidence for a functional role of c-Myb in altered growth, androgen-independence and malignant behavior of the prostate cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2156. doi:10.1158/1538-7445.AM2011-2156