This disease of breast cancer (BrCa) has been intensively studied over the past quarter century, yet major gaps remain in our understanding of causal mechanisms operating at the level of molecules, cells and tissues; these shortfalls continue to compromise our ability to predict malignant progression of primary BrCa's and identify novel targets for clinical intervention. This Project involves an interacting consortium o BrCa researchers who intend to uncover causative mechanisms operating at a succession of steps of tumor development. One project examines how defects in the BRCA1 protein generate the mutations that create mutant BrCa cell genomes in genetically predisposed patients and in a portion of sporadic tumors. A second examines how the reproductive history of women interacts with the differentiation of distinct cell types to increase or reduce BrCa formation. A third studis how the hormonal environment of a woman together with the actions of the BRCA1 gene lead to changes in gene regulation, the outgrowth of these tumors, and the acquisition of resistance to existing therapies.. A fourth examines how signals released by oncoproteins affect the cell-cycle apparatus and how these signaling channels offer a striking opportunity for therapeutic intervention. A fifth will determine whether distinct subpopulations of carcinoma cells within primary BrCa's collaborate with one another in enabling tumor growth, while a six examines how signals released by the BrCa-associated stroma induce primary BrCa cells to acquire traits of highly malignant cells that enable them to invade and metastasize. This last program becomes highly relevant to reducing BrCa-associated mortality, since the vast majority of deaths derive from the metastases generated by these tumors rather than from primary growths within the breast. Together, the proposed Projects hold the promise of elucidating key steps in tumor formation that have offered or will offer novel molecular targets for therapeutic intervention.

Public Health Relevance

Breast cancer is a complex disease involving multiple distinct types of cancer cells arising from distinct types of cells in the normal breast. The succession of steps that leads from normal breast tissue to high-grade, malignant tumors is still poorly understood at multiple levels, limiting our ability to develop reliable markers that predict the future course of disease and novel agents for treating this disease. This Program examines multiple steps in the process of breast tumor development that must be resolved before new types of predictive markers and novel therapeutic strategies can be developed.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Woodhouse, Elizabeth
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Whitehead Institute for Biomedical Research
United States
Zip Code
Zhang, Jinfang; Xu, Kai; Liu, Pengda et al. (2016) Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt. Mol Cell 62:929-42
Spiegel, Asaf; Brooks, Mary W; Houshyar, Samin et al. (2016) Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells. Cancer Discov 6:630-49
Shu, Shaokun; Lin, Charles Y; He, Housheng Hansen et al. (2016) Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529:413-7
Hydbring, Per; Malumbres, Marcos; Sicinski, Piotr (2016) Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat Rev Mol Cell Biol 17:280-92
De Cock, Jasmine M; Shibue, Tsukasa; Dongre, Anushka et al. (2016) Inflammation Triggers Zeb1-Dependent Escape from Tumor Latency. Cancer Res 76:6778-6784
Malorni, Luca; Giuliano, Mario; Migliaccio, Ilenia et al. (2016) Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance. Mol Cancer Res 14:470-81
Fu, Xiaoyong; Jeselsohn, Rinath; Pereira, Resel et al. (2016) FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proc Natl Acad Sci U S A 113:E6600-E6609
Huh, Sung Jin; Oh, Hannah; Peterson, Michael A et al. (2016) The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women. Cancer Res 76:1926-34
Wang, Hua; Bierie, Brian; Li, Andrew G et al. (2016) BRCA1/FANCD2/BRG1-Driven DNA Repair Stabilizes the Differentiation State of Human Mammary Epithelial Cells. Mol Cell 63:277-92
Goel, Shom; Wang, Qi; Watt, April C et al. (2016) Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 29:255-69

Showing the most recent 10 out of 114 publications