Abstract 4545: Lyn tyrosine kinase regulates androgen receptor expression and activity in prostate cancer

Abstract

Abstract Background: Prostate Cancer (PCa) is the most common cancer in North America and the second leading cause of cancer-related death in men. Early detection and treatment of localized PCa has improved, however, many men still die of metastatic disease. While androgen ablation remains the most effective management option for patients with advanced disease, most will suffer disease progression to castrate resistant prostate cancer (CRPC) within 2 years of treatment initiation. CRPC progression is a complex process by which cells acquire the ability to survive and proliferate in the absence of androgens. It is proposed that tumors develop mechanisms, which re-activate the androgen receptor (AR) axis via oncogenic pathways, in which tyrosine kinases play a crucial role. Hence, the development of small inhibitory drugs targeting Src family tyrosine kinases (SFK) such as Dasatinib has opened a new window for therapeutic interventions. Although enthusiasm for these approaches remains high, prostate tumor heterogeneity, redundancy in signaling pathways and non specificity of such inhibitors, dictate the need to better understand mechanisms linking SFK to CRPC progression. Genetic manipulation of several tyrosine kinases in vivo revealed that only a knockout of Lyn compromised prostate gland development suggesting that Lyn plays a critical role in prostate development. Lyn has been shown to be expressed in colon cancer and PCa cell lines and over-expression of its constitutive active form confers resistant to chemotherapeutic agents. Given that AR plays a central role in normal prostate development and in proliferation and survival of PCa cells, we sought to investigate the role of Lyn on AR expression and activity. Method: Human specimens from untreated and CRPC were submitted to Immunohistochemistry using Lyn antibody. LNCaP and C4-2 cells were treated or not with siRNA against Lyn and submitted to Western blot and qRT-PCR analysis. Cells transfected with Lyn WT and dominant negative (DN) as well as siRNA were tested for their ability to modulate AR transcription activity using PSA luciferase reporter promoter. Results: We found that Lyn expression correlates with PCa progression to CRPC in both in vitro and in vivo. Lyn is up-regulated in androgen independent C4-2 compared to androgen dependent LNCaP and is highly expressed in CRPC compared to naive tumors. Targeting Lyn expression or activity using short interfering RNA or dominant negative abrogates AR transcription activity while its overexpression enhances it. Interestingly, we found that suppressing Lyn expression using siRNA results in a decrease of AR protein expression thereby a decrease in PSA expression. Conclusion: Together, these results suggest that Lyn plays a role in CRPC development and that inhibiting Lyn expression could be considered as a potential therapeutic target for CRPC. 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 4545. doi:10.1158/1538-7445.AM2011-4545