Abstract 3291: Upregulation of Insulin Receptor Substrate-2 (IRS-2) expression by hypoxia

Abstract

Abstract Insulin Receptor Substrate-2 (IRS-2) belongs to the IRS family of cytoplasmic adaptor proteins that mediate signaling from cell surface receptors, including growth factor, cytokine and integrin receptors. Many of these receptors have been implicated in cancer. Although the IRS proteins are highly homologous in structure and have some complementary functions, growing evidence supports that the IRS proteins have unique roles in cancer. IRS-1 has been shown to promote tumor cell proliferation, while IRS-2 has been positively associated with tumor cell motility and invasion. Previously, our lab demonstrated that Polyoma Middle T-derived Irs-2−/− mouse mammary tumors are significantly less metastatic, and Irs-1−/− tumors significantly more metastatic, than their wild-type counterparts. In recent studies, we observed that IRS-2 expression increases in response to hypoxia in both metastatic mouse mammary tumor cells and poorly differentiated ER-negative metastatic human breast carcinoma cells. In contrast, IRS-1 expression does not increase in response to hypoxia, supporting the notion of their non-overlapping functions. Hypoxia promotes the adaptation and resistance of cancer cells to chemo- and radiation therapy, and also promotes tumor cell survival, invasion and metastasis by selecting for aggressive tumor cells that can survive under stressful low oxygen conditions. We have also shown that IRS-2 upregulation in response to hypoxia promotes tumor cell viability and invasion, selecting for tumor cells with increased metastatic potential. To understand how IRS-2 is regulated by hypoxia, we identified a minimal 200 bp region of the IRS-2 promoter located 700 bp upstream from the translation start site that is hypoxia-responsive. Mutation of an E-box binding site within this region that has been previously implicated in regulating IRS-2 in response to hormone stimulation inhibits hypoxic upregulation of IRS-2. We are currently investigating the factors that bind to this E-box to regulate IRS-2 expression. In addition, we have established that HIF is required for IRS-2 upregulation in hypoxic environments, and we are investigating if HIF acts in a direct or indirect manner to regulate IRS-2 expression. Identifying the mechanism by which IRS-2 expression is regulated by hypoxia is essential for developing novel methods to inhibit IRS-2 expression to suppress metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3291.