IRS1 is highly expressed in localized breast tumors and regulates the sensitivity of breast cancer cells to chemotherapy, while IRS2 is highly expressed in invasive breast tumors

• IRS1 and pSTAT6 are highly expressed in ductal carcinoma in situ.
• IRS2 expression correlates with increasing grade of invasive ductal carcinoma.
• MCF7 cells are more sensitive to taxol-induced death than MDA-MB-231 cells.
• Decreasing IRS1 de-sensitizes MCF7 cells to several chemotherapeutic agents.
• Decreasing IRS1 in MCF7 cells decreases ERalpha expression levels.

Insulin receptor substrate (IRS) proteins have been shown to play an important role in breast cancer by differentially regulating cancer cell survival, proliferation, and motility. Furthermore, the IL-4-induced tyrosine phosphorylation of the transcription factor STAT6 was shown to protect breast cancer cells from apoptosis. Here, we analyzed human breast cancer tissues for the expression of IRS1, IRS2, STAT6, and tyrosine phosphorylated STAT6 (pSTAT6). We found that IRS1 and pSTAT6 were both highly expressed in ductal carcinoma in situ (DCIS). On the other hand, IRS2 expression was low in DCIS, but increased significantly in relation to tumor invasiveness. We utilized cell lines with disparate IRS1 expression, MDA-MB-231, MCF7, and MCF7 cells with depleted IRS1 due to shRNA lentiviral infection, to examine the role of IRS1 and IRS2 in the responsiveness of breast cancer cells to chemotherapy. We report that high IRS1 sensitized MCF7 cells to specific chemotherapeutic agents. These results suggest that high IRS1 with low IRS2 expression may predict the effectiveness of specific types of chemotherapy in breast cancer.