Abstract 4871: Obesity-mediated regulation of HGF/c-Met and reduced basal-like breast cancer latency in parous mice
Authors: Sundaram Sneha , Freemerman Alex J. , Kirk Erin L. , Galanko Joseph A. , McNaughton Kirk K. , Bendt Katharine M. , Darr David B. , Troester Melissa A. , Makowski Liza 
Published: May 2015

Background: Epidemiologic and experimental data have shown that a full term pregnancy reduces breast cancer risk. 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. BBC represents &lt;10% of breast cancers, are highly aggressive, affecting primarily young and African-American women. Experimental studies have examined parity and obesity individually, but to date, the independent and joint effects of parity and obesity have not been dissected. Our previous work demonstrated that high fat diet-induced obesity significantly blunted BBC latency in nulliparous C3(1)-Tag mice, potentially through the hepatocyte growth factor (HGF)/c-Met oncogenic pathway. Since obesity and post-partum weight gain are sometimes difficult to parse out, we investigated the role of obesity in parous mice on BBC. Methods: Seven week old female C3(1)-TAg mice were placed with male mice for breeding. Males were removed at pregnancy and pups were removed immediately after birth. The mothers were then randomly assigned to diet groups to model post-partum obesity. Mice were fed control low fat diet (10% kcal from fat) or high fat diet (45% or 60% kcal from fat) at 10 weeks until sacrifice. Mice were monitored for fat accretion, tumor onset, and tumor progression. Plasma measures of cytokines and metabolic parameters were assessed. Immunohistochemical analyses for HGF, c-Met and F4/80 macrophage markers were performed. Results: Mice on both 45% and 60% diets gained significantly greater fat mass compared to mice remaining lean on 10% diet. Compared with nulliparous mice fed the same diets, parity induced significant decreases in latency in C3(1)-TAg mice fed 10% and 45% diets. 60% diet reduced latency in parous mice to the same extent as nulliparous mice fed 60% diet. Tumor burden and tumor aggressiveness were not regulated by obesity in parous mouse. Obesity-associated metabolic mediators and hormones such as insulin, estrogen, and progesterone were not significantly regulated however, leptin levels were elevated in 45%-fed mice compared to other groups. Plasma IL-6 was significantly elevated by obesity in parous mice. Importantly, the HGF/c-Met axis in normal mammary gland was elevated significantly by obesity and correlated with reduced tumor latency.

Conclusions: In summary, our studies demonstrate that, similar to epidemiologic reports, parity in C3(1)-TAg mice alone dramatically reduced BBC latency compared to nulliparous mice. Obesity in parous mice did not reduce latency further than obesity alone, indicating that obesity and parity may work through similar pathways. Finally, obesity induced c-Met expression in normal mammary gland in parous mice, similar to our reports in nulliparous mice, implicating an interaction between the HGF/c-Met signaling pathway and obesity in the etiology of BBC.

Citation Format: Sneha Sundaram, Alex J. Freemerman, Erin L. Kirk, Joseph A. Galanko, Kirk K. McNaughton, Katharine M. Bendt, David B. Darr, Melissa A. Troester, Liza Makowski. Obesity-mediated regulation of HGF/c-Met and reduced basal-like breast cancer latency in parous mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4871. doi:10.1158/1538-7445.AM2014-4871