Role of HGF in obesity-associated tumorigenesis: C3(1)-TAg mice as a model for human basal-like breast cancer.
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)-T(Ag) 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.
Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, CB 7461, 2203 McGavran Greenberg Hall, Chapel Hill, NC, 27599-7461, USA, sundaras@live.unc.edu.
Sneha
S
Sundaram
Alex J
AJ
Freemerman
Amy R
AR
Johnson
J Justin
JJ
Milner
Kirk K
KK
McNaughton
Joseph A
JA
Galanko
Katharine M
KM
Bendt
David B
DB
Darr
Charles M
CM
Perou
Melissa A
MA
Troester
Liza
L
Makowski
D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000401:mortality / Q000473:pathology; D002280:Basal Cell Carcinoma / Q000209:etiology / Q000401:mortality / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000150:complications* / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015398:Signal Transduction
D016207:Cytokines; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met