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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA080111-16
Application #
8609151
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Mohla, Suresh
Project Start
1999-03-18
Project End
2019-01-31
Budget Start
2014-05-02
Budget End
2015-01-31
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Witwicki, Robert M; Ekram, Muhammad B; Qiu, Xintao et al. (2018) TRPS1 Is a Lineage-Specific Transcriptional Dependency in Breast Cancer. Cell Rep 25:1255-1267.e5
Jeselsohn, Rinath; Bergholz, Johann S; Pun, Matthew et al. (2018) Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations. Cancer Cell 33:173-186.e5
Hinohara, Kunihiko; Wu, Hua-Jun; Vigneau, S├ębastien et al. (2018) KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance. Cancer Cell 34:939-953.e9
Wan, Lixin; Xu, Kexin; Wei, Yongkun et al. (2018) Phosphorylation of EZH2 by AMPK Suppresses PRC2 Methyltransferase Activity and Oncogenic Function. Mol Cell 69:279-291.e5
Xiao, Tengfei; Li, Wei; Wang, Xiaoqing et al. (2018) Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy. Proc Natl Acad Sci U S A 115:7869-7878
Zhang, Jinfang; Bu, Xia; Wang, Haizhen et al. (2018) Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553:91-95
Li, Andrew G; Murphy, Elizabeth C; Culhane, Aedin C et al. (2018) BRCA1-IRIS promotes human tumor progression through PTEN blockade and HIF-1? activation. Proc Natl Acad Sci U S A 115:E9600-E9609
Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro E et al. (2018) Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2-ER?-GREB1 Transcriptional Axis. Cancer Res 78:671-684
Dreijerink, Koen M A; Timmers, H T Marc; Brown, Myles (2017) Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. Endocr Relat Cancer 24:T135-T145
Rashidian, Mohammad; Ingram, Jessica R; Dougan, Michael et al. (2017) Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med 214:2243-2255

Showing the most recent 10 out of 136 publications