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

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

Research output: Contribution to journalArticle

72 Citations (Scopus)

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 languageEnglish
Pages (from-to)1416-1427
Number of pages12
JournalCancer Research
Volume72
Issue number6
DOIs
Publication statusPublished - Mar 15 2012

Fingerprint

Leptin
Estrogen Receptors
Breast Neoplasms
Growth
Neoplasms
Obesity
Leptin Receptors
Stromal Cells
Epidermal Growth Factor
Cell Communication
Cell Movement
Protein Isoforms
Cytokines
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Barone, I., Catalano, S., Gelsomino, L., Marsico, S., Giordano, C., Panza, S., ... Andò, S. (2012). Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells. Cancer Research, 72(6), 1416-1427. https://doi.org/10.1158/0008-5472.CAN-11-2558

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 journalArticle

Barone, I, Catalano, S, Gelsomino, L, Marsico, S, Giordano, C, Panza, S, Bonofiglio, D, Bossi, G, Covington, KR, Fuqua, SAW & Andò, S 2012, 'Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells', Cancer Research, vol. 72, no. 6, pp. 1416-1427. https://doi.org/10.1158/0008-5472.CAN-11-2558
Barone I, Catalano S, Gelsomino L, Marsico S, Giordano C, Panza S et al. Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells. Cancer Research. 2012 Mar 15;72(6):1416-1427. https://doi.org/10.1158/0008-5472.CAN-11-2558
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. / Leptin mediates tumor-stromal interactions that promote the invasive growth of breast cancer cells. In: Cancer Research. 2012 ; Vol. 72, No. 6. pp. 1416-1427.
@article{432b30af5e13410484d1cf16c60c3183,
title = "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.",
author = "Ines Barone and Stefania Catalano and Luca Gelsomino and Stefania Marsico and Cinzia Giordano and Salvatore Panza and Daniela Bonofiglio and Gianluca Bossi and Covington, {Kyle R.} and Fuqua, {Suzanne A W} and Sebastiano And{\`o}",
year = "2012",
month = "3",
day = "15",
doi = "10.1158/0008-5472.CAN-11-2558",
language = "English",
volume = "72",
pages = "1416--1427",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84858266343&partnerID=8YFLogxK

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 -