Crosstalk Between Leptin Receptor and IGF-IR in Breast Cancer: A Potential Mediator of Chemoresistance

Obesity is a major risk factor for the development and progression of breast cancer, and is associated with reduced treatment response and reduced overall survival. The obesity-associated hormones IGF-I and leptin are found at high levels in the serum of breast cancer patients, and their receptors, IGF-IR and the leptin receptor Ob-R are overexpressed in a majority of breast tumor tissues. We have discovered by co-immunoprecipitation that IGF-IR and Ob-R physically interact in breast cancer cells. This interaction was associated with cross talk from IGF-IR to Ob-R, as IGF-I stimulation promoted signaling downstream of the leptin receptor, including increased phosphorylation of Ob-R, STAT3, and JAK2. Our preliminary data suggests that this cross talk is unidirectional, as leptin stimulation did not alter IGF-IR phosphorylation. Our ongoing studies will examine this cross talk in more detail, in part by determining the biological and molecular effects of inhibition of these growth factor receptors. We will then examine the influence of this cross talk on response to taxane-based chemotherapy.