We showed that when IGF-II is highly expressed in breast tissues and cell lines the IGF-1 receptor signaling pathway is highly activated. Since IGF-II activates the insulin receptor (INSR), we propose that the INSR signaling is also activated in this system. We examined the expression of both INSR isoforms, INSR-A, INSR-B, and the downstream signaling pathways in breast cancer cells and in paired (normal/tumor) breast tissues from 100 patients. Analysis was performed by Real Time-PCR, Western blot, immunohistochemistry and Phospho-ELISA techniques. Tumor tissues and cell lines from African American patients (AA) expressed higher levels of INSR-A, but lower levels of INSR-B. In accordance, IRS-1 and FAK activation were significantly increased in these women. We conclude that higher INSR-A and lower INSR-B contributes to higher proliferation and lower metabolic response. Thus, differential expression of INSR isoforms represents a potential biological link between breast cancer and diabetes.