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.
| Original language | English |
|---|---|
| Pages (from-to) | 1416-1427 |
| Number of pages | 12 |
| Journal | Cancer Research |
| Volume | 72 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Mar 15 2012 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells. / Barone, Ines; Catalano, Stefania; Gelsomino, Luca; Marsico, Stefania; Giordano, Cinzia; Panza, Salvatore; Bonofiglio, Daniela; Bossi, Gianluca; Covington, Kyle R.; Fuqua, Suzanne A W; Andò, Sebastiano.
In: Cancer Research, Vol. 72, No. 6, 15.03.2012, p. 1416-1427.Research output: Contribution to journal › Article
}
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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UR - http://www.scopus.com/inward/citedby.url?scp=84858266343&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-11-2558
DO - 10.1158/0008-5472.CAN-11-2558
M3 - Article
VL - 72
SP - 1416
EP - 1427
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 6
ER -