Leptin Mediates Tumor-Stromal Interactions That Promote the Invasive Growth of Breast Cancer Cells

Obesity confers risks to cancer development and progression but the mechanisms underlying these risks remain unclear. In this study, we identify a role for the obesity cytokine leptin, which has been implicated previously in breast cancer development, as a determinant for the tumor-promoting activity of cancer-associated fibroblasts (CAF) in both wild-type(WT) and K303R mutant estrogen receptor-a (ER alpha)-expressing breast cancer cells. Human CAFs stimulated a greater increase in the proliferation and migration of breast cancer cells expressing the K303R-ER alpha hyperactive receptor than WT-ER alpha-expressing cells. A concomitant increase was seen in leptin receptor isoform expression and activation of the leptin signaling pathway in cells expressing K303R-ER alpha compared with WT-ER alpha, correlating with lep tin effects on cell growth, motility, and invasiveness in mutant cells. Epidermal growth factor and other factors secreted by K303R-ER alpha cells stimulated CAP proliferation, migration, and subsequent leptin secretion. Moreover, K303R-ER alpha expression generated a leptin hypersensitive phenotype in vivo. Together, our results reveal a bidirectional cross-talk between breast cancer cells and "educated" CAF's that drives tumor progression via leptin signaling. In elucidating a mechanism that connects obesity and cancer, these findings reinforce the concept that blocking cancer-stromal cell communication may represent an effective strategy for targeted therapy of breast cancer. Cancer Res; 72(6); 1416-27. (C) 2012 AACR