Abstract 1968: Obesity-induced activation of the androgen receptor

Abstract

Abstract Background: Prostate cancer is the second leading cause of cancer deaths for men in the US. Obesity increases the risk of dying from prostate cancer by almost 50%. The mechanisms by which obesity promotes a more aggressive disease remain largely unknown, hindering the development of effective approaches for improving patient outcome. It is hypothesized that because obesity is associated with elevated circulating levels of growth factors, activation of the androgen receptor may be responsible for the increased risk of a more aggressive cancer in obese men. This current study investigates the effects of obese sera on androgen receptor activity in a highly novel prostate cancer cell line. Methods: LNCaP prostate cancer cells were stably infected with a lentiviral Dual-Luciferase reporter plasmid containing an androgen receptor response element (ARE). These stable ARE-reporter cells were then exposed to sera from either obese or control weight mice. Specific signal transduction inhibitors were used to determine the role of growth factor signaling in mediating the effects observed in response to exposure to the different sera. Results: Exposure to obese sera activated the androgen receptor to levels three-fold greater than those seen with control sera. Intriguingly, use of a PI3 kinase inhibitor reduced obesity-induced activation of the AR by 75%, but only by 64% in the control sera. Studies are on-going to determine the role of both the Akt and MAPK pathways in these results, as well as the relative contribution of circulating androgens in activating the AR. Downstream targets of the AR induced by exposure to the obese sera are being identified both by Western blot and microarray analyses. Conclusions: These results suggest that obesity-related circulating factors induce activation of the androgen receptor in prostate cancer cells. This activation appears to be both ligand dependent (androgens) and ligand independent (growth factors). These data suggest that one mechanism by which obesity influences time to progression and hormone independence is through activation of the androgen receptor. 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 1968. doi:10.1158/1538-7445.AM2011-1968