Human mammary organotypic cultures for chemical screening
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: Non-technical overview of the research topic and relevance to breast cancer: Geographic and social disparities in breast cancer incidence indicate that environmental agents such as chemicals can influence this disease. Knowledge of these agents and how they act to promote breast cancer is needed so that exposures can be minimized and breast cancers prevented. Currently, however, the vast majority of chemicals found in homes and workplaces have not been safety-tested. Moreover, the tests that are available are too slow and expensive to screen the tens of thousands of chemicals to which people are exposed, and/or the tests detect surrogate endpoints, such as toxicity, with unclear relevance to breast cancer. Assays conducted with cultured cells offer some advantages over animal studies because: a) human cells can be used, b) tests can be performed quickly and cheaply using automated equipment, and c) confounding variables can be minimized. However, breast cancer is not a disease of individual cells, but a collective failure of cells and tissues to communicate properly. 
 
 
 
 
 
 Malignant transformation of breast cells is a complex multi-stage process, which occurs over long periods of time, and involves cumulative changes. The challenge therefore is to develop cell culture assays that effectively model the cell communication processes that go awry in breast cancer, so that the assays can be used to assess the effects of chemicals on these processes, and ultimately gauge the risks of human exposure. Another aspect of the project is to translate research that shows how hormones affect breast cancer risk into tools useful for evaluating risks from chemicals that act like hormones or disrupt hormone function. 
 
 
 
 
 
 Research question(s) or central hypotheses: We hypothesize that we can use discarded normal human breast tissue to obtain adult stem cells - immature cells that can develop into specialized cells, and then grow them in the lab into miniature organs (organoids) useful for detecting carcinogenic changes. 
 
 
 
 
 
 General methodology: The project will be roughly divided into 3 parts. First, we will a) generate large uniform quantities of human mammary stem cells and b) get them to form organized structures containing the main specialized cell types found in normal breast tissues. We will use standard techniques to determine the extent to which the cultures use the same genes and make the same proteins as those in human breast tissues. Second, we will expose the organoid cultures to 18 chemicals that have or have not been shown to cause mammary tumors in rodent studies (our benchmark), and determine which changes predict a chemical’s carcinogenicity or give clues about how the chemical affects the breast. We will also use genetic manipulation of the cells to mimic common mutations known to contribute to breast cancer, and test whether hormonally active chemicals cause the cells to show carcinogenic changes. Third, we will use knowledge gained from these experiments and additional published information to build mechanistic models of the interactions of hormones and DNA-damaging carcinogens in the breast so that chemical testing and risk assessment methods can predict the effects of such chemicals. These tools are crucial for screening the backlog of chemicals already in homes and workplaces, as well as newly developed chemicals, and reducing or eliminating the use of those chemicals that pose the greatest risks.
 
 
 
 
 
 Innovative elements: Although stem cell-derived models that mimic tissue structures and function have been made for other organs, none have been developed for human breast. Being able to see whether chemicals produce carcinogenic changes by altering cell-cell interactions and developmental processes will be an important advance both practically and conceptually.
 
 
 
 
 
 Advocacy involvement and relevance to the human issues associated with breast cancer: The research team assembled for the proposed project has a track record of research in partnership with breast cancer advocates. The PI and advocate partner Zero Breast Cancer have collaborated previously on an NCI/NIEHS-funded Breast Cancer and Environment Research Center; while Silent Spring Institute was founded by breast cancer advocates specifically to conduct community-based participatory research on environmental factors in breast cancer. For this proposed project, we will collaborate with Zero Breast Cancer to develop an educational toolkit, including a short video for lay audiences, describing how chemicals can affect development of breast cancer. In addition, representatives from four California Breast Cancer organizations (Breast Cancer Action, Breast Cancer Fund, Zero Breast Cancer, and Noreen Fraser Foundation) will participate in an advisory group for the CBCRP chemicals testing program that will give the advocates direct access to researchers and government scientists involved in development of 21st century chemicals testing approaches. 
 
 
 
 
 
 
 
 Publications: 
 
 
 
 Berkeley Lab Scientists to Develop Better Way to Screen Chemicals for Cancer-Causing Effects