Pregnancy weight gain and risk of mammary cancer among rat dams and their female offspring.

摘要

Breast cancer risk is affected not only by the factors to which a woman is exposed, but also when in her life-time these exposures occur. In this thesis, I investigated the effects of excessive weight gain during pregnancy on rat mammary tumorigenesis among mothers and their female offspring.; First, I studied the effects of exposure to estradiol or leptin---hormones associated with weight gain---on dam's mammary tumorigenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA). Leptin, but not estradiol, increased the incidence of mammary tumors when compared to the vehicle-controls. Both of these exposures also increased mammary epithelial density and cell proliferation, and led to changes in signaling pathways regulating processes such as angiogenesis and cell proliferation.; Next, I examined whether excessive weight gain during pregnancy increased DMBA-induced mammary tumorigenesis in Sprague-Dawley, leptin receptor mutant (and therefore obese) and wildtype Zucker rats. Pregnant rats were fed either a control diet or an obesity-inducing high fat diet (OID); the OID increased pregnancy leptin (but not estradiol) levels and pregnancy weight gain. Additionally, the OID increased mammary tumorigenesis in all genetic backgrounds. Thus, the elevated breast cancer risk, at least in the mutant Zucker rats, had to be mediated by mechanisms other than activation of the leptin receptor. Mammary tumorigenesis was higher in the mutant than in the wildtype Zucker rats, suggesting that even in the absence of functional leptin receptor, obesity is associated with increased mammary tumorigenesis.; Finally, I examined whether high birth weight induced by maternal exposure to the OID increased the female offspring's DMBA-induced mammary tumorigenesis. Compared to the controls, rats with high birth weight exhibited shortened mammary tumor latency and accelerated tumor growth. The changes in tumorigenesis were associated with elevated levels of terminal end buds (TEBs), proliferating cells and MAPK activation as well as reduced ERalpha levels in the mammary gland.; I have demonstrated that excessive weight gain during pregnancy or an exposure to leptin increases mammary tumorigenesis in rat dams and their female offspring. Future studies are needed to determine the mechanisms by which high pregnancy leptin levels increases breast cancer risk.