A novel biological framework for the role of xenoestrogens
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Xenoestrogens (XEs) are known to elicit estrogen like effects. Long banned in the United States, the pesticide DDT is a well-known example of this class of compounds. Like many XEs, it exerts physiological effects, whereby genetic males grow to look like females externally. Since excessive exposure to estrogen is believed to increase the risk of breast cancer, it seems likely that agents, such as XEs that mimic the effects of this hormone may confer similar risks in the human population. In recent studies it has been demonstrated that cells in laboratory dishes when exposed to bisphenol A (BPA), a chemical used to make the type of plastics commonly used in disposable beverage bottles, display a pattern of gene activation similar to that induced by estrogens. A major limitation of previous data relevant to tumor initiation is that it is based on the XE response of cancer cell lines. These cells are already malignant and have undergone decades of selection for survival and rapid growth in the laboratory. They are thus biologically far removed from the normal target tissue of individuals who may be at an increased risk for breast cancer development due to inadvertent exposure to excessive XE levels in their environment. The key aspect of our project is to study the molecular changes induced by XEs directly in live cells within nonmalignant breast tissue of high-risk individuals.
 
 
 
 
 
 
 
 To circumvent the disadvantages of an incremental learning process requiring translation from cancer cell line and/or animal work to human disease induced by environmental agents, such as XEs, here we propose two innovative approaches:
 
 
 
 1) Simulating the exchange of molecular signals that occur within breast tissue by using a co culture set up of normal human breast epithelial cells and stromal fibroblasts,
 
 
 
 2) Employing live, normal breast cells collected from non-cancerous contralateral tissue of breast cancer patients by random periareolar fine needle aspiration (RPFNA).
 
 
 
 
 
 
 
 In conjunction with gene chip technology optimized by our collaborators at Stanford University, these novel cellular systems will be used to identify a gene ‘signature’ depicting response to the widely pervasive XE, BPA. We will then ask whether the changes in gene expression induced by BPA can be reversed with the estrogen antagonist, tamoxifen.
 
 
 
 
 
 
 
 This proposal is aimed at addressing the widespread concern among individuals, families, and society at large regarding regions of California where the incidence of breast cancer is significantly higher, potentially due to environmental factors. It is anticipated that assays based on target human cells will be significantly more reliable in screening chemicals that pose a specific threat to human health. We hope to delineate a small well-defined set of genetic markers, such that exposure to various XEs might be readily identified. Ultimately, the analysis of these markers in clinical tumor tissue could reliably distinguish individuals exposed to excessive XE levels. Such data will be invaluable for capturing new and effective molecular targets to assist in cancer prevention.