title: Obesity-mediated regulation of HGF/c-Met is associated with reduced basal-like breast cancer latency in parous mice.
abstract: It is widely thought that pregnancy reduces breast cancer risk, but this lacks consideration of breast cancer subtypes. While a full term pregnancy reduces risk for estrogen receptor positive (ER+) and luminal breast cancers, parity is associated with increased risk of basal-like breast cancer (BBC) subtype. Basal-like subtypes represent less than 10% of breast cancers and are highly aggressive, affecting primarily young, African American women. Our previous work demonstrated that high fat diet-induced obesity in nulliparous mice significantly blunted latency in C3(1)-TAg mice, a model of BBC, potentially through the hepatocyte growth factor (HGF)/c-Met oncogenic pathway. Experimental studies have examined parity and obesity individually, but to date, the joint effects of parity and obesity have not been studied. We investigated the role of obesity in parous mice on BBC. Parity alone dramatically blunted tumor latency compared to nulliparous controls with no effects on tumor number or growth, while obesity had only a minor role in further reducing latency. Obesity-associated metabolic mediators and hormones such as insulin, estrogen, and progesterone were not significantly regulated by obesity. Plasma IL-6 was also significantly elevated by obesity in parous mice. We have previously reported a potential role for stromal-derived hepatocyte growth factor (HGF) via its cognate receptor c-Met in the etiology of obesity-induced BBC tumor onset and in both human and murine primary coculture models of BBC-aggressiveness. Obesity-associated c-Met concentrations were 2.5-fold greater in normal mammary glands of parous mice. Taken together, our studies demonstrate that, parity in C3(1)-TAg mice dramatically reduced BBC latency compared to nulliparous mice. In parous mice, c-Met is regulated by obesity in unaffected mammary gland and is associated with tumor onset. C3(1)-TAg mice recapitulate epidemiologic findings such that parity drives increased BBC risk and potential microenvironmental alterations in c-Met signaling may play a role in etiology.
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Sneha
authors.initials: S
authors.lastname: Sundaram
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Alex J
authors.initials: AJ
authors.lastname: Freemerman
authors.affiliation: UNC Nutrition Obesity Research Center, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Medicine, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Galanko
authors.affiliation: Department of Cell and Molecular Physiology, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Kirk K
authors.initials: KK
authors.lastname: McNaughton
authors.affiliation: Mouse Phase I Unit, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Katharine M
authors.initials: KM
authors.lastname: Bendt
authors.affiliation: Mouse Phase I Unit, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: David B
authors.initials: DB
authors.lastname: Darr
authors.affiliation: Lineberger Comprehensive Cancer Center, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America; Departments of Epidemiology, and Pathology and Laboratory Medicine, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.affiliation: UNC Nutrition Obesity Research Center, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Medicine, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Nutrition, Gillings School of Global Public Health and School of Medicine, UNC Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Liza
authors.initials: L
authors.lastname: Makowski
mesh_terms: D000818:Animals; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000097:blood; D008325:Mammary Neoplasms, Experimental / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009765:Obesity / Q000150:complications / Q000378:metabolism*; D010298:Parity; D013997:Time Factors
chemical_list: C553307:HGF protein, mouse; D015850:Interleukin-6; D017228:Hepatocyte Growth Factor