Dietary modulation of estrogen-induced mammary and pituitary tumorigenesis in the female rat

Estrogens are important regulators of cell proliferation in several tissues and have been implicated in the etiology of specific types of cancer including the breast and benign tumors of the anterior pituitary. The goal of this dissertation was to investigate the mechanisms through which estrogens induce mammary and pituitary tumorigenesis and how these processes are affected by environmental factors such as the diet. We examined the hypothesis that dietary factors inhibit tumorigenesis in estrogen responsive tissues by altering cellular responsiveness to estrogenic hormones. First, we investigated the mechanisms through which estrogens contribute to mammary tumor development by comparing the actions of 17β-estradiol (E2) on cell proliferation and lobuloalveolar development in the mammary glands of two genetically related rats strains, the ACI and Copenhagen (COP). Previously, we reported that ACI and COP rats both develop E2-induced pituitary tumors but exhibit diametrically opposed susceptibilities to E2-induced mammary tumors. We now demonstrate that the mammary epithelium of the highly susceptible ACI rat exhibits a more robust proliferative response to E2 than does the highly resistant COP rat, suggesting a possible mechanism for the observed differences in E2-induced mammary tumor susceptibility between these strains. We also examined the ability of an energy-restricted diet to inhibit E2-induced mammary tumorigenesis in the ACI rat. The hypothesis tested was that energy restriction would inhibit mammary turnorigenesis even when circulating E2 remained elevated through administration of exogenous hormone. We demonstrate that dietary energy restriction inhibits E2-induced mammary, but not pituitary, tumorigenesis in the ACI rat. We also examined the effects of energy restriction on E2-induced pituitary growth in the COP rat. Our data indicate dietary energy restriction markedly inhibits E2-induced pituitary growth in this strain. Inhibition appears to occur through a mechanism involving an inhibition of E2-stimulated pituitary cell proliferation and not survival. Together, these data indicate energy restriction modulates the responsiveness of specific cell populations to estrogenic hormones and thereby inhibits E2-induced turnorigenesis in a tissue and strain specific manner.