Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells
Menée sur deux lignées cellulaires de cancer du sein, cette étude met en évidence le rôle de la leptine, une cytokine associée à l'obésité, dans la régulation des interactions entre une tumeur et le stroma favorisant la croissance tumorale
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 (CAFs) in both wild-type (WT) and K303R mutant ERα-expressing breast cancer cells. Human CAFs stimulated a greater increase in the proliferation and migration of breast cancer cells expressing the K303R ERα hyperactive receptor than wild-type ERα-expressing cells. A concomitant increase was seen in leptin receptor isoform expression and activation of the leptin signaling pathway in cells expressing K303R ERα compared to wild-type ERα, correlating with leptin effects on cell growth, motility and invasiveness in mutant cells. EGF and other factors secreted by K303R ERα cells stimulated CAF proliferation, migration, and subsequent leptin secretion. Moreover, K303R ERα expression generated a leptin hypersensitive phenotype in vivo. Together, our results reveal a bi-directional crosstalk between breast cancer cells and 'educated' CAFs which 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.