Journal
CANCER RESEARCH
Volume 72, Issue 6, Pages 1416-1427Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-2558
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Funding
- Reintegration AIRC/Marie Curie International Fellowship in Cancer Research
- Lilli Funaro Foundation
- European Commission/FSE/Regione Calabria
- AIRC [1G11595, IG8804]
- NCI [RO1 CA72038]
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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
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