TY - JOUR
T1 - Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells
AU - Barone, Ines
AU - Catalano, Stefania
AU - Gelsomino, Luca
AU - Marsico, Stefania
AU - Giordano, Cinzia
AU - Panza, Salvatore
AU - Bonofiglio, Daniela
AU - Bossi, Gianluca
AU - Covington, Kyle R.
AU - Fuqua, Suzanne A W
AU - Andò, Sebastiano
PY - 2012/3/15
Y1 - 2012/3/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-11-2558
DO - 10.1158/0008-5472.CAN-11-2558
M3 - Article
C2 - 22282662
AN - SCOPUS:84858266343
VL - 72
SP - 1416
EP - 1427
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 6
ER -