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|ERRgamma-dependent mammary tumorigenesis in response to BPA and a high-fat diet|
Diet-induced obesity, insulin (INS) resistance, and type 2 diabetes have reached epidemic proportion among women in the United States, and each of these health problems significantly increase a woman s risk of developing breast cancer. Studies linking exposure to the endocrine disruptor Bisphenol A (BPA) with mammary tumorigenesis in rodents, poor survival outcome and response to chemotherapy in human breast cancer, and an increased risk for diabetes and INS resistance are suggestive of a shared signaling network responsive to this ubiquitous environmental contaminant. BPA readily crosses the placental barrier, appears to accumulate in the fetus, and is found in breast milk. However, very little is known about the molecular mechanisms that regulate breast cancer development in response to co-morbidities like obesity and INS resistance, or how BPA functions in this context. |
While the true molecular target of BPA has been debated for some time, it is now known that this compound can bind with high affinity and specificity to the orphan nuclear receptor estrogen-related receptor gamma (ERRgamma).
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 ERRgamma 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 ERRgamma cDNA mimics BPA s effect on HK2, suggesting that BPA-mediated changes in vivo are likely to be ERRgamma-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 ERRgamma, 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 ERRgamma allele.
Aim 2 will study ERRgamma, HK2, and PDK4 expression changes in the mammary glands and tumor tissues of ERRgamma +/- 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.
This project is generously funded by an R03 from the Cancer Prevention Research Small Grant Program (NCI).
||ERRgamma, BPA, insulin resistance, breast cancer risk
|Regulation of ERRgamma in endocrine resistant breast cancer by the ERK pathway|
Breast cancer is not a single disease. There are several different types that can be separated by their physical and genetic features. Invasive ductal breast carcinomas have historically been the most common type of breast cancer. However, the frequency of invasive lobular breast carcinoma (ILC) diagnosis has been increasing significantly in Western Europe and the U.S. over the past 10-15 years. ILCs most commonly express estrogen receptor alpha (ER), which in many cases is a marker for good prognosis and a sign that these patients are excellent candidates for treatment with antiestrogens like Tamoxifen, or an aromatase inhibitor. Surprisingly, women with ER-positive ILC do not always experience significantly better survival than women with ER-positive ductal tumors when both groups are treated with antiestrogens. |
The reasons for this discrepancy are almost entirely unknown, and unfortunately the current laboratory models that are used to study antiestrogen resistance have all been derived from ductal carcinomas. To address this deficiency, we have developed a breast cancer cell culture model of invasive lobular carcinoma that has become resistant to the antiestrogen Tamoxifen. In this model we have found that increased expression of the gene estrogen related receptor gamma (ERRgamma) plays an essential role in Tamoxifen resistance, and that its function is likely to be modified or changed by the activity of a second gene, extracellular signal-regulated kinase (ERK).
The idea we will be testing is that ERK regulates ERRgamma's function in TAM-resistant breast cancer. In Specific Aim 1, we will use our new cell culture model of invasive lobular carcinoma to understand how ERK regulates or modifies ERRgamma function and whether this explains how these breast cancer cells have become resistant to Tamoxifen. In Specific Aim 2 we will look more closely at ERRgamma expression in breast tumor specimens from 150 patients with ductal and lobular breast cancer in order to determine whether high expression of this gene is linked to poor overall survival, poor response to Tamoxifen, and the activity of ERK.
This project is generously supported by a grant from Susan G. Komen for the Cure.
||Invasive Lobular Carcinoma, Tamoxifen, ERRgamma, ERK
Cancer Res. 2008 Nov 1. 68(21):8908-17.