The increasing rates of breast cancer occuring in developed countries has been tentatively linked to elevated exposure to endocrine disrupting agents. One such agent, bisphenol A (BPA), is a component of plastics and resins that leaches into food and beverage products and has been detected in normal human serum, amniotic fluid, and fetuses. BPA has estrogenic properties both in vitro and in vivo and pre- or perinatal treatment of rodents promotes inappropriate development and proliferation of mammary gland alveoli in adults. While this mammary gland response portends a predilection for development of mammary cancer, no studies have been reported that directly assess whether mammary cancer susceptibility is indeed altered following BPA exposure. Our central hypothesis is that prenatal exposure to bisphenol A will increase mammary gland tumor susceptibility in adult mice. We predict that this increase in susceptibility will be due to combined developmental changes both within the gland and in the hormonal milieu. During formation of the mammary anlagen, an altered estrogenic environment may convey an irreversible adaptive response, making the gland intrinsically more susceptible to the formation of hyperplasia, a preneoplastic state. In addition to altering end organ sensitivity, we expect a central change in the endocrine environment of BPA exposed females. We anticipate that these factors collaborate, creating an altered transcriptome that predisposes the mammary gland to carcinogenic events later in life. We will directly assess the tumor susceptibility of mammary glands that prenatally exposed to BPA using a chemical carcinogen paradigm. We also will determine if chronic hyperplasia induced by BPA is due to intrinsic mammary epithelial changes, hormonal alterations, or both. Lastly, we will characterize changes in the mammary gland transcriptome that integrate these inputs to form a hyperplastic gland. This will build a foundation for future work examining mechanisms by which expression of these genes/pathways is changed by prenatal BPA exposure as well as determining if overt manipulation of these genes alters breast cancer risk.
| Weber Lozada, Kristen; Keri, Ruth A (2011) Bisphenol A increases mammary cancer risk in two distinct mouse models of breast cancer. Biol Reprod 85:490-7 |
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