Breast Cancer Research and Treatment

, Volume 142, Issue 3, pp 489–503 | Cite as

Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer

  • Sneha Sundaram
  • Alex J. Freemerman
  • Amy R. Johnson
  • J. Justin Milner
  • Kirk K. McNaughton
  • Joseph A. Galanko
  • Katharine M. Bendt
  • David B. Darr
  • Charles M. Perou
  • Melissa A. Troester
  • Liza Makowski
Preclinical Study

Abstract

Obesity is associated with basal-like breast cancer (BBC), an aggressive breast cancer subtype. The objective of this study was to determine whether obesity promotes BBC onset in adulthood and to evaluate the role of stromal–epithelial interactions in obesity-associated tumorigenesis. We hypothesized that hepatocyte growth factor (HGF) plays a promoting role in BBC, which express the HGF receptor, c-Met. In C3(1)-TAg mice, a murine model of BBC, we demonstrated that obesity leads to a significant increase in HGF secretion and an associated decrease in tumor latency. By immunohistochemical analysis, normal mammary gland exhibited obesity-induced HGF, c-Met and phospho-c-Met, indicating that the activation of the cascade was obesity-driven. HGF secretion was also increased from primary mammary fibroblasts isolated from normal mammary glands and tumors of obese mice compared to lean. These results demonstrate that obesity-induced elevation of HGF expression is a stable phenotype, maintained after several passages, and after removal of dietary stimulation. Conditioned media from primary tumor fibroblasts from obese mice drove tumor cell proliferation. In co-culture, neutralization of secreted HGF blunted tumor cell migration, further linking obesity-mediated HGF-dependent effects to in vitro measures of tumor aggressiveness. In sum, these results demonstrate that HGF/c-Met plays an important role in obesity-associated carcinogenesis. Understanding the effects of obesity on risk and progression is important given that epidemiologic studies imply a portion of BBC could be eliminated by reducing obesity.

Keywords

Basal-like breast cancer Tumor latency Microenvironment Normal mammary gland High fat diet-induced obesity Fibroblast 

Abbreviations

BBC

Basal-like breast cancer

HGF

Hepatocyte growth factor

BMI

Body mass index

ER

Estrogen receptor

PR

Progesterone receptor

HER2

Human epidermal growth factor-2

NAF

Normal-associated fibroblasts

CAF

Cancer-associated fibroblasts

Notes

Acknowledgments

We thank the directors and personnel of the UNC LCCC Mouse Phase One Unit (MP1U) for assistance with animal handling, therapeutic studies, and tumor serial assessment. Work in the MP1U was supported by the University Cancer Research Fund. This publication was made possible by the Breast Cancer and the Environment Research Program (BCERP) Award Number U01ES019472 from the National Institute of Environmental Health Sciences (NIEHS) and the National Cancer Institute (NCI), NIH, DHHS. LM was supported by UNC University Cancer Research Fund, NIH AA017376; NIH ES019472; NIH P30DK056350—Nutrition Obesity Research Consortium (NORC); NIH P30DK034987 Center for GI Biology and Disease. MAT was supported by NIH ES019472 and RO1-CA138255. JAG was supported by NIH Grants DK034987 and DK056350. CMP was supported by funds from the NCI Breast SPORE Program (P50-CA58223-09A1), by RO1-CA138255 and RO1-CA148761.

Conflict of interest

C. M. Perou holds a pending patent assignment for PAM50 Genomic Classifier. He also holds a position on the Board of Directors as well as Stock ownership in University Genomics and Bioclassifier. All other authors declare no conflict of interest.

Supplementary material

10549_2013_2741_MOESM1_ESM.docx (1.5 mb)
Supplementary material 1 (DOCX 1572 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Sneha Sundaram
    • 8
  • Alex J. Freemerman
    • 8
  • Amy R. Johnson
    • 8
  • J. Justin Milner
    • 8
  • Kirk K. McNaughton
    • 5
  • Joseph A. Galanko
    • 1
    • 7
  • Katharine M. Bendt
    • 2
  • David B. Darr
    • 2
    • 3
  • Charles M. Perou
    • 2
    • 3
    • 4
  • Melissa A. Troester
    • 1
    • 3
    • 6
  • Liza Makowski
    • 1
    • 3
    • 7
    • 8
  1. 1.UNC Nutrition Obesity Research Center, Gillings School of Global Public Health and School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  2. 2.Mouse Phase I Unit, School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Departments of Genetics, and Pathology and Laboratory Medicine, School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  5. 5.Department of Cell and Molecular Physiology, School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  6. 6.Departments of Epidemiology, and Pathology and Laboratory Medicine, Gillings School of Global Public Health and School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  7. 7.Department of Medicine, School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA
  8. 8.Department of Nutrition, Gillings School of Global Public Health and School of MedicineUniversity of North Carolina at Chapel HillChapel HillUSA

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