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.
Highlights
Epidemiologic and experimental data have shown that a full term pregnancy reduces breast cancer risk [1]
Using nulliparous C3(1)-T antigen (TAg) mice, a unique genetically engineered murine model (GEMM) of basallike breast cancer (BBC) [4,34], we reported that obesity reduced latency and induced tumor cell aggressiveness, which is the first work in preclinical models paralleling human epidemiologic BBC findings [35]
We have previously shown that stromalderived hepatocyte growth factor (HGF/scatter factor) and its cognate receptor c-Met correlated with obesity-induced BBC tumor onset in nulliparous mice [22] and were reduced with weight loss [21]
Summary
Epidemiologic and experimental data have shown that a full term pregnancy reduces breast cancer risk [1]. BBCs are estrogen receptor-, progesterone receptor- and human epidermal growth factor receptor 2 (HER2)- negative, often referred to as triple-negative breast cancers, and as such these cancers lack a targeted therapy [5]. Patients have poor overall survival because these tumors are highly proliferative. Tumors are diagnosed predominantly in young African-American women, obese women [6,7,8]. While a full term pregnancy reduces risk for estrogen receptor-positive breast cancers, like the luminal subtype [1], parity is associated with increased probability of developing the more aggressive basallike breast cancer (BBC) subtype [7,9,10,11,12]
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