P2-03-03: An Insulin-Like Growth Factor I (IGF-I)-Induced Gene, Solute Carrier Family 7 Member 11 (SLC7A11)/xCT, Mediates IGF-I-Induced Biological Behaviors in Breast Cancer Cells.

Abstract Our laboratory studied the gene expression profiles of a series of T47D variant cell lines with differential insulin receptor substrate (IRS) adaptor protein expression to develop predictive IGF-I pathway biomarkers. We identified an IGF-I-induced gene, SLC7A11 (or xCT), which is specifically regulated through IRS-1. xCT encodes the cystine/glutamate transporter subunit of the heterodimeric amino acid transport system xc- which is a major plasma membrane transporter for the cellular uptake of cystine in exchange for intracellular glutamate. xCT is involved in the regulations of proliferation, metastasis, and drug resistance in various cancers. However, to date, the linkage between xCT and the IGF-I signaling pathway has not been described. To study the role for xCT in mediating IGF-I-induced biology in breast cancer cell lines, we examined xCT mRNA expression upon IGF-I stimulation in two breast cancer cell lines; the MCF-7 (IRS-1 activated) and MDA-MB-231 (IRS-2 activated) cells. Significant increased xCT expression was observed only in MCF-7 cells after IGF-I treatment. Immunoblots showed that xCT protein expression was elevated after IGF-I treatment and induced glutamate/cystine exchange in MCF-7 cells. shRNA was used to downregulate xCT in MCF-7 and MDA-MB-231 cells. In MCF-7, IGF-I-stimulated cell monolayer growth was suppressed by xCT shRNA or by the xCT inhibitor sulfasalazine (SASP). In MDA-MB-231 cells, xCT downregulation did not affect IGF-mediated Boyden chamber migration. Thus, IGF-I induction of cellular xCT levels is associated with cell growth in the IRS-1 activated MCF-7 cells, while MDA-MB-231 cells were not affected by downregulation of this gene. Therefore, our data imply that xCT may mediate IGF-I induced biological functions in breast cancer cell lines through an IRS-1 dependent pathway. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-03-03.