Xenoestrogen-specific perturbations in the human breast
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: Introduction: To prevent breast cancer, it is critical to acquire the knowledge of events that occur in benign (non-malignant) cells before they become cancerous (malignant). To this end, we have developed live interactive processes to evaluate the effects of potentially carcinogenic chemicals on non-malignant human breast cells that can be studied experimentally. We have already demonstrated that environmental chemicals cause dramatic changes in cell programming, which are similar to the effects of estrogens. Since estrogens are involved in the origins of breast cancer, it is important to regulate the use of chemicals that mimic this hormone, also known as xenoestrogens (XEs). For example, the well-known carcinogen, stilbestrol or DES, is an estrogen mimic. Our major goal is to employ non-malignant cells in assays to screen chemicals for estrogen-like effects. 
 
 
 
 
 
 
 
 Central hypothesis: We hypothesize that continued exposure of non-malignant breast cells to XEs - at levels already reported in mother’s blood, cord blood, placenta, mother’s milk and human tissue - alters central functions of cell metabolism, and redirects exposed cells on the path to cancer. 
 
 
 
 
 
 
 
 General methodology: Using bisphenol A (BPA) as a test chemical, we have previously identified six sets of genes that are significantly affected in human breast cells. These changes, which allow damaged cells to survive and acquire additional defects, predict specific functional deficiencies also found within aggressive breast tumors. Our goal is to build on these findings in 3 steps: (1) Define consistent changes caused by a wide panel of known XEs in non-malignant breast cells using established cell biology assays. This will establish a basic battery of tests to screen unknown chemicals, which might behave as XEs. (2) Apply novel technologies and computational approaches to enhance the understanding of XE-induced functional changes thereby facilitating the development of additional tests. This will allow an expanded choice of reliable screens from a comprehensive battery of assays for XE effects. (3) Apply our ability to obtain significant data from small numbers of cells within clinical samples to develop assays utilizing readily renewable and repeatedly available sources of non-malignant breast cells such as human milk. 
 
 
 
 
 
 
 
 Innovative elements: In the public debate on the safety of chemicals, providing a recommendation is often a dilemma for scientists who are skeptical of arbitrary end points without a clear understanding of why or how biological effects of XEs, such as the feminization of animals, or enhanced growth activity in breast cancer cell lines, come about. We address scientific skepticism by identifying a series of simple metabolic functions that can define pertinent cancer related effects - or lack of effects -- of a chemical on human cells. We have already shown that four inter-related attributes of breast cancer (oxidative stress, metabolic pathway signaling, apoptosis, and proliferation) consistently occur after exposure of living cells to BPA, and to another possible XE - methylparaben. Our innovative approach to ascertain these and other functional changes at the cellular level provides the needed mechanistic framework for whole animal studies and advances standardized XE screening, as well as breast cancer prevention research. To extend the study of tiny samples from human breast tissue to younger women who are closer to the earliest steps of carcinogenesis, and to establish other renewable sources of breast epithelium for carcinogenicity research, we will optimize techniques we have already used to grow stem cells present in human milk. 
 
 
 
 
 
 
 
 Community involvement: Our central aim is to develop unequivocal criteria to differentiate between chemicals that exert estrogenic effects and those that do not. To make research data widely available, we have already actively disseminated our results to the lay press, public forums, and the broadcast media. To fulfill the overall goal of disease prevention, we will work closely with MORE GREEN MOMS, an advocacy group that is focused on environmental exposure of the most vulnerable members of society – our children. We have also actively supported others in the field, such as the collaborative between the Natural Resources Defense Council and UC Berkeley School of Public Health in a CBCRP-sponsored effort to define the current status of chemical tests for breast cancer. Our present proposal is a focused response to the recommendations of that initiative. Finally, to engage a wide representation of community leadership in this cause, we have proactively sought the support of business and professional leaders outside of usual advocacy groups.