SAN FRANCISCO—Researchers at the California Pacific Medical Center said their observations warranted the need to reinforce the concern bisphenol-A (BPA) and methylparaben (MP), at low concentrations detected in humans, can have adverse health consequences, suggesting an increased risk of breast cancer, an estrogen driven disease (Carcinogenesis. Sept. 1, 2011). Treatments for menopausal symptoms such as hormone replacement therapy (HRT) have correlated with disease incidence; however, increasing male breast cancer rates over the past three decades implicate additional sources of estrogenic exposure, including wide spread estrogen-mimicking chemicals or xenoestrogens (XEs), such as BPA, commonly found in plastics. By exposing renewable, human, high-risk donor, breast epithelial cells (HRBECs) to BPA at concentrations that are detectable in human blood, placenta and milk, researchers previously identified gene expression profile changes associated with activation of mammalian target of rapamycin (mTOR) pathway genesets likely to trigger pro-survival changes in human breast cells, which now provide functional validation of mTOR activation using pair wise comparisons of 16 independent HRBEC samples with and without BPA exposure.
Researchers demonstrate induction of key genes and proteins in the PI3K-mTOR pathway—AKT1, RPS6 and 4EBP1—and a concurrent reduction in the tumor suppressor, PTEN protein. Altered regulation of mTOR pathway proteins in BPA-treated HRBECs led to marked resistance to rapamycin, the defining mTOR inhibitor. Moreover, HRBECs pretreated with BPA, or the XE, MP, surmounted anti-estrogenic effects of tamoxifen showing dose-dependent apoptosis evasion and induction of cell cycling. Overall, XEs, when tested in benign breast cells from multiple human subjects, consistently initiated specific functional changes of the kind that are attributed to malignant onset in breast tissue.