Differential expression and signaling activation of insulin receptor isoforms A and B: A link between breast cancer and diabetes

Abstract

We showed that when insulin-like growth factor II (IGF-II) is highly expressed in breast tissues and cell lines, the IGF-I 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, insulin receptor A (INSR-A) and insulin receptor B (INSR-B), and the downstream signaling pathways in breast cancer (BC) 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 expressed higher levels of INSR-A, but lower levels of INSR-B. Accordingly, insulin receptor substrate 1 and focal adhesion kinase activation were significantly increased in these women. We conclude that higher INSR-A and lower INSR-B contribute to higher proliferation and lower metabolic response. Thus, differential expression of INSR isoforms represents a potential biological link between BC and diabetes.

Keywords::

• Breast cancer
• IGF
• insulin receptor A
• insulin receptor B
• cell signaling

Acknowledgment

This research was supported by 5P20 MD001632 and NIGMS 5R25GM060507. Anti-INSR α-subunit (5D9) rabbit polyclonal antibody was kindly provided by Dr R. Roth, Stanford University, Stanford, CA, USA.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.