Regulation of breast cancer cell motility by insulin receptor substrate-2 (IRS-2) in metastatic variants of human breast cancer cell lines

Insulin-like growth factors (IGFs) regulate breast cancer cell proliferatio n, protect cells from apoptosis, and enhance metastasis. In this study, we examined the IGF signaling pathway in two breast cancer cell lines selected for metastatic behavior. LCC6 was, selected for growth as, an ascites tumo r in athymic mice from parental MDA-MB-435 cells (435P). The MDA-231BO cell line was derived from osseous metastases that formed after intracardiac in jection of the MDA-MB-231 cell line in athymic mice. Compared to the parent al cell Rues, IGF-I treatment enhanced IRS-2 phosphorylation over IRS-I in the metastatic variants. IGF-I stimulated cell migration in the variant cel ls, but not in the parental cells. To. determine the role for IRS-2 in IGF- mediated motility, we transfected MDA-231BO cells with, an anti-sense IRS-2 construct. Transfected cells had decreased levels of IRS-2. with diminishe d IGF-mediated motility and anchorage independent growth when compared to c ontrol cells. However, adherence to fibronectin was. enhanced in the transf ected cells compared to MD A-231BO cells. Our data show that breast cancer cells selected for metastatic behavior in vivo have increased IRS-2 activat ion and signaling. In these cells, IGF-I enhances cell adhesion and motilit y suggesting that IRS-2 may mediate these aspects of the malignant phenotyp e.