Riggins Lab:Notebook/Cancer Prevention R03
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In our preliminary studies, we have found that a neonatal exposure to BPA impairs glucose tolerance in 2-month-old female Sprague Dawley rats, suggestive of early INS resistance, and hepatic expression of ERRγ and two of its putative target genes (hexokinase 2, HK2; pyruvate dehydrogenase kinase 4, PDK4) are increased by BPA exposure in these animals. HK2 and PDK4 are essential enzymes of glycolysis, dysregulation of which is implicated in diabetes, INS resistance, and cancer. BPA also increases the expression of HK2 and PDK4 in MCF10A normal human mammary epithelial cells, and transient overexpression of ERRγ cDNA mimics BPA’s effect on HK2, suggesting that BPA-mediated changes in vivo are likely to be ERRγ-dependent.
Our central hypothesis is that early life exposure to BPA increases later mammary cancer risk by reducing INS sensitivity, and that this is mechanistically dependent upon ERRγ, which we will test in two Specific Aims: Aim 1 will test whether early life exposure to BPA and subsequent exposure to a high-fat diet reduces INS sensitivity and increases mammary tumorigenesis in wildtype mice, and whether this is reduced or fails to occur in mice exhibiting loss of one ERRγ allele. Aim 2 will study ERRγ, HK2, and PDK4 expression changes in the mammary glands and tumor tissues of ERRγ+/- mice and their wildtype counterparts to determine whether the activity of this glycolytic signaling network is associated with the INS resistance and tumorigenicity measures from Aim 1.