Crosstalk Between Leptin Receptor and IGF-IR in Breast Cancer: A Potential Mediator of Chemoresistance
EMORY UNIV ATLANTA GA
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Obesity is a major risk factor for breast cancer, and is associated with reduced treatment response and reduced overall survival. The obesity-associated hormones IGF-I and leptin and their receptors, IGF-IR and leptin receptor Ob-R, are elevated in breast cancer. Co-immunoprecipitation and immunoblotting demonstrated that IGF-IR and Ob-R interact in the breast cancer cell lines MDA-MB-231, MCF7, BT474, and SKBR3. Stimulation of cells with IGF-I promoted Ob-R phosphorylation, which was blocked by IGF-IR kinase inhibition. In addition, IGF-I activated downstream signaling molecules in the leptin receptor and IGF-IR pathways. In contrast to IGF-I, leptin did not induce phosphorylation of IGF-IR, indicating that receptor cross signaling is unidirectional, occurring from IGF-IR to Ob-R. Our results demonstrate for the first time a novel interaction and cross talk between the IGF-I and leptin receptors in human breast cancer cells. Our data also showed that inhibition of JAK2, which is immediately downstream of the leptin receptor, reduced proliferation of MCF7 breast cancer cells. Leptin specifically reduced sensitivity to docetaxel, and not to targeted therapies trastuzumab or lapatinib. Further, an unrelated obesity-associated cytokine did not reduce docetaxel sensitivity, suggesting that chemoresistance may be specifically induced by leptin and not by all adipocytokines.
- Medicine and Medical Research