title: 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.
abstract: 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.
authors.affiliation: Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Porter
authors.forename: Anthony
authors.initials: A
authors.lastname: Perry
authors.forename: Chris
authors.initials: C
authors.lastname: Kingsley
authors.forename: Nhan L
authors.initials: NL
authors.lastname: Tran
authors.forename: Achsah D
authors.initials: AD
authors.lastname: Keegan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002278:Carcinoma in Situ / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis* / Q000235:genetics; D061986:MCF-7 Cells; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D017239:Paclitaxel
keywords: Breast cancer; Cell death; Chemotherapy; Insulin receptor substrate; STAT6
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