This research is focused on the molecular mechanisms that govern whether a primary breast cancer will or will not become aggressive, metastatic and thus life threatening. At present, the ability to predict such aggressiveness is imperfect, in that there is great inter-individual variability in the behavior of a group of tumors that are all classified together in one of the major subgroups of breast cancer and thus predicted to share a common prognosis. At present, this inability to generate accurate predictions of the future behavior of individual breast cancers leads to aggressive treatment of the great majority of diagnosed tumors, when only a minority are destined to become life threatening. The research describes three major determinants of malignant progression of breast cancer cells and how they conspire to generate aggressive behavior. These are (i) the ability of carcinoma cells to release pro-inflammatory signals;(ii) the reciprocal responses of nearby mesenchymal stem cells within the stroma of tumors to these carcinoma-derived signals, resulting secondarily in the release of signals that have the potential of inducing carcinoma cells to move from an epithelial(benign) to mesenchymal (malignant) state;and (iii) the propensity of the carcinoma cells to respond to these stroma-derived signals by undergoing this shift in differentiation state, thereby acquiring highly aggressive characteristics. The propensity of cancer cells to move from an epithelial/benign to a mesenchymal/malignant state appears to be governed by the state of the chromatin associated with the gene that encodes ZEB1, which functions as the key molecular governor of the epithelial vs. mesenchymal states. Examining the chromatin configuration of this gene- more specifically the covalent modifications of the histones associated with the promoter of this gene - holds the promise of revealing the proclivity of a breast cancer cell to activate its program of malignant conversion, often termed the epithelial-mesenchymal transition.

Public Health Relevance

This research is focused on the molecular mechanisms that determine whether or not a primary human breast cancer will become aggressive and metastatic, resulting in an ability to predict such future behavior. At present, the inability to predict this behavior results in the vast overtreatment of breast cancer patients, most of whom are treated with aggressive therapies even though the tumors that they bear are not destined to ever become life threatening.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA080111-16
Application #
8633703
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2014-05-02
Budget End
2015-01-31
Support Year
16
Fiscal Year
2014
Total Cost
$281,039
Indirect Cost
$44,103
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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