Timing of Dietary Exposures on Risk of Reproductive Cancer

Abstract

TIMING OF DIETARY EXPOSURES ON RISK OF REPRODUCTIVE CANCER

Elissa J. Carney, M.S.

Thesis Advisor: Leena Hilakivi-Clarke, PhD.

ABSTRACT

The effect of dietary factors on breast cancer risk is largely determined by when during her life-time a woman is exposed to them. This dissertation encompasses three investigations of whether the timing of dietary exposures also determines their effect on reproductive tract cancers. Furthermore, the molecular mechanisms mediating the effects of dietary exposures during in utero, prepuberty, and adulthood on risk of endometrial or uterine cancer risk were investigated. First, I investigated whether prepubertal dietary intake of phytoestrogen genistein in soy foods alters ovarian cancer risk in 7, 12 dimethylbenz(a)anthracene (DMBA) treated mice which model women carriers of germline BRCA1 mutations. Prepubertal genistein diet reduced the incidence of granulosa cell tumors in Brca1+/- and wildtype mice. This effect was associated with reduced levels of estrogen receptor alpha, cell proliferation, and increased apoptosis. Second, I investigated whether lifetime or adult genistein intake can prevent tamoxifen-induced endometrial carcinogenesis in outbred Sprague Dawley rats. One third of tamoxifen treated rats developed premalignant endometrial lesions. Adult intake of genistein prevented lesions was associated with reduced ER-alpha levels and altered cytochrome P450 (CYP) signaling, suggesting a reduction in the formation of carcinogenic estrogen metabolites. The unfolded protein response was activated by tamoxifen in the uterus; however, genistein intake did not modify this response. Lastly, I investigated the effects of maternal exposure to obesity-inducing high fat diet or adipose-tissue derived adipokine leptin during pregnancy on offspring's risk of endometrial carcinogenesis in Pten+/- and wild type mice. Pten+/- mice exposed to leptin in utero had significantly higher risk of developing premalignant endometrial lesions than control mice, but this effect was not related to persistent changes in leptin signaling in the endometrium. Through these preclinical studies, I have demonstrated the significance of timing of dietary exposures on cancer risk in the female reproductive tract. I also have shown that the changes in cancer risk are associated with persistent alterations in the pathways that mediate cell proliferation and apoptosis. Findings obtained in these studies are translatable to preventing reproductive tract cancers in women by making dietary modifications involving consumption of soy foods.