[摘要]：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
