Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. Exposures to environmental agents can have an effect on mammary gland development and may affect breast cancer risk. This project explores the mechanisms underlying windows of susceptibility during across the lifespan. By defining the molecular architecture of the developing and changing mammary gland over the lifespan the investigators will be able to develop new and improved animal models and biomarkers to study the Impact of environmental stressors on breast cancer, elucidate the effects of timing of exposure during critical windows of vulnerability in both normal and tumor prone animals. This project will use state-of-the-art imaging, proteomic and genetic tools to determining when, which and how environmental insults regulate cell behavior in the mouse mammary gland during development in vivo, and in conversion of mammary epithelial cells to premalignant phenotypes. Experiments will be conducted cooperatively, using organotypic cultures and mouse models to characterize pathways related to breast development during early life, puberty, pregnancy, and other time points, and to determine how they are affected by exposures to environmental stressors occurring at different windows of vulnerability. These studies in mice will be complemented using human breast epithelium in culture to develop new assays that can assess how exogenous agents alter their ability to overcome finite lifespan and constraints imposed by intercellular interactions. By defining critical windows of vulnerability, and creating improved animal and human cell culture models that will lead to identification of biomarkers, these studies have the potential for translation to women to determine the impact of environmental stressors on breast cancer. The investigators propose to determine the alterations in the mechanical properties of mammary microenvironment in mice in vivo and the mammary epithelial cells during the life cycle. The investigators will determine the effects of exposure to prototypical environmental stressors during the life cycle on the mammary gland in normal and cancer prone mice in vivo and in human breast specimens. They will use in vitro mechanism-based assays to detect agents that possess signatures indicative of possible mammary gland carcinogenicity. This project will participate in the BCERP Network activities by exchange of information, interactions and collaborations. An essential feature of this proposal is regular bidirectional communication with the community-based advocacy group to focus on appropriate environmental stressors and to develop biomarkers and to translate the findings into lay terms.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-LKB-V (02))
Program Officer
Reinlib, Leslie J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Anatomy/Cell Biology
Schools of Medicine
San Francisco
United States
Zip Code
Chou, Jonathan; Chan, Matilda F; Werb, Zena (2016) Metalloproteinases: a Functional Pathway for Myeloid Cells. Microbiol Spectr 4:
Williams, Katherine E; Lemieux, George A; Hassis, Maria E et al. (2016) Quantitative proteomic analyses of mammary organoids reveals distinct signatures after exposure to environmental chemicals. Proc Natl Acad Sci U S A 113:E1343-51
Horiuchi, Dai; Camarda, Roman; Zhou, Alicia Y et al. (2016) PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression. Nat Med 22:1321-1329
Lemieux, George A; Cunningham, Katherine A; Lin, Lin et al. (2015) Kynurenic acid is a nutritional cue that enables behavioral plasticity. Cell 160:119-31
Hines, William C; Yaswen, Paul; Bissell, Mina J (2015) Modelling breast cancer requires identification and correction of a critical cell lineage-dependent transduction bias. Nat Commun 6:6927
Tung, Jason C; Barnes, J Matthew; Desai, Shraddha R et al. (2015) Tumor mechanics and metabolic dysfunction. Free Radic Biol Med 79:269-80
Block, Keith I; Gyllenhaal, Charlotte; Lowe, Leroy et al. (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl:S276-S304
Acerbi, I; Cassereau, L; Dean, I et al. (2015) Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb) 7:1120-34
Northcott, Josette M; Northey, Jason J; Barnes, J Matthew et al. (2015) Fighting the force: Potential of homeobox genes for tumor microenvironment regulation. Biochim Biophys Acta 1855:248-53
Werb, Zena; Lu, Pengfei (2015) The Role of Stroma in Tumor Development. Cancer J 21:250-3

Showing the most recent 10 out of 37 publications