Abstract 4014: Differential expression and activation of IRS1 and IRS2 in breast cancer cell lines

Abstract

Abstract Numerous studies have shown that IL-4 can protect various types of tumor cells from chemotherapeutic agents including breast cancer cells. There are two main signaling pathways activated by IL-4; the STAT6, signal transducers and activators of transcription pathway, that results in expression of IL-4-responsive genes and the IRS1/2 signaling pathway that influences cellular proliferation and survival. IL-4 can act directly on many tumor cell types to prevent apoptosis. The IL-4-induced activation of STAT6 has been shown to up-regulate anti-apoptotic proteins, cFlip and BcLxL, in cancer. IRS1/2 molecules link the IL-4R and IGF-1R to signaling pathways that regulate cellular proliferation and survival, and are therefore implicated in cancer progression. Recent studies showed that IRS2 regulates mammary tumor metastasis in a mouse model of breast cancer and that knocking out IRS2 rendered the tumor cells less invasive and more susceptible to apoptosis in response to growth factor withdrawal. IRS1 was not required for metastasis and was actually suggested to be a suppressor of metastasis in breast cancer and an enhancer of proliferation. IRS2 suppressed the function of IRS1 by strongly activating the Akt/mTOR signaling pathway and inducing the serine phosphorylation of IRS1. We have found that expression of IRS1, in contrast to IRS2, leads to enhanced sensitivity to chemotherapy-induced cell death in 32D cells. Furthermore, it has been shown that MCF7 cells are more sensitive to docetaxel-induced death as compared to MDA-MB-231 cells. We propose that sensitivity of breast cancer cells to chemotherapy is in part regulated by the relative abundance of IRS1 and IRS2 and their phosphorylation status. To begin to test this hypothesis, we cultured breast cancer cells lines in the presence or absence of IL-4 and evaluated the IRS pathways. We found that MCF7 cells highly expressed IRS1 with little IRS2 while MDA-MB-231 cells expressed relatively equal amounts of IRS1 and IRS2. In MCF7 cells IL-4 induced the potent tyrosine phosphorylation of IRS1 with very little tyrosine phosphorylation of IRS2. However, in MDA-MB-231 cells, IL-4 induced the tyrosine phosphorylation of both IRS1 and IRS2 equally. However, the level of IRS1 phosphorylation in MDA-MD-231 cells was less than that observed in MCF7 cells. Taken together with previous publications, these results suggest that the differential activation status of IRS1 and IRS2 in breast cancer can lead to differential metastatic and chemosensitivity phenotypes. 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 4014.