Within North America, prostate cancer is the most commonly diagnosed cancer in men with devastating implications deriving from metastasis, particularly those established in the bone. We have elucidated mechanisms by which prostate cancer undergoes metastasis with particular focus on the relationship between extracellular-matrix binding proteins, Integrin B1 (ITGB1) and epithelial-to-mesenchymal transition (EMT). Previous results in the laboratory suggested that prostate tumor cells depleted of ITGB1 were unable to form colonies in soft agarose and were impaired in their invasive abilities in vitro. In order to determine the possible mechanisms by which ITGB1 controlled these phenotypes, we performed numerous genetic techniques including siRNA targeted depletion of ITGB1 and subsequent profiling of pathway specific message RNA by RTqPCR to monitor the effects ITGB1 depletion on factors known to control EMT which is also associated with cell invasion. We found that prostate tumor cells depleted of ITGB1 had altered expression of numerous genes associated with EMT or cell invasion, many of which have been validated by RT-qPCR and western blot. In particular, a protease inhibitor SERPINE1 also known as Plasminogen Activator Inhibitor 1 (PAI-1) which is associated with EMT has been established as a target of ITGB1 regulation, in part via the ability of ITGB1 to regulate upstream factors associated with SERPINE1 expression such as TGFB2. Of particular interest to prostate cancer bone metastasis, we further found that collagen I interacting with ITGB1 significantly upregulated this pathway, and given the known role of EMT in mediating resistance to anti-cancer agents, this finding could help elucidate novel targets for the development of new drugs to treat prostate cancer bone metastasis.
Citation Format: Steven R. Bugiel, Elisabeth McKittrick, Huijun Zhao, Grant A. Howe, Christina L. Addison. Extracellular matrix-integrin B1 signaling is a major mediator of epithelial-to-mesenchymal transition and contributes to prostate cancer invasion and metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1121. doi:10.1158/1538-7445.AM2014-1121