Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells.

Abstract

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-α (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 WT-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 with WT-ERα, correlating with leptin effects on cell growth, motility, and invasiveness in mutant cells. Epidermal growth factor 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 bidirectional cross-talk between breast cancer cells and "educated" CAFs 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.

• Authors: Ines Barone, Stefania Catalano, Luca Gelsomino, Stefania Marsico, Cinzia Giordano, Salvatore Panza, Daniela Bonofiglio, Gianluca Bossi, Kyle R Covington, Suzanne A W Fuqua, Sebastiano Andò
• Journal: Cancer research (Cancer Res) Vol. 72 Issue 6 Pg. 1416-27 (Mar 15 2012) ISSN: 1538-7445 [Electronic] United States
• PMID: 22282662 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ESR1 protein, human
• Estrogen Receptor alpha
• Leptin
• Receptors, Leptin
• Epidermal Growth Factor

Topics

• Breast Neoplasms (pathology)
• Carcinoma (pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Epidermal Growth Factor (metabolism)
• Estrogen Receptor alpha (analysis)
• Female
• Fibroblasts (physiology)
• Gene Expression Profiling
• Humans
• Leptin (physiology)
• Neoplasm Invasiveness
• Receptors, Leptin (analysis)
• Signal Transduction
• Stromal Cells (physiology)