In this project we propose to continue our ongoing work relating to how defective function of the BRCA1 gene results in breast cancer development. Specifically, we propose to ask the following questions. 1) Do specific molecular defects in the response to DNA double DNA strand breaks (DSB) exist in the tumor cells of sporadic basal like breast cancers(BLC)? BLC is a relatively common, BRCA 1 wt, phenocopy of BRCA1 mutant disease. If such defects exist, do any affect the operation of DSB response pathways to which BRCA1 normally makes a major contribution? 2) Is the BRCA1-IRIS protein, an alternatively spliced BRCA1 gene product, a protooncoprotein? If so, does its oncoprotein function contribute to the development of certain subtypes of sporadic breast cancer and, if so, how? 3) In a normal setting, BRCA 1 p220 is present and readily detectable in the nucleus both during the G1 and S/G2 cell cycle phases. It is less abundant in G1 than in S in some cell lines. Moreover, although it localizes after ionizing radiation (IR) in special nuclear foci (so called IRIF) in S/G2, it fails to do so in G1, even though these foci contain a protein (Rap80) that normally participates in tethering BRCA 1 to these structures. We seek to understand the molecular basis for this difference between G1 and S/G2 and, if deciphered, to probe its physiological significance, especially with respect to how it might relate to the normal regulation of BRCA1 DNA repair function.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA080111-15
Application #
8449505
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2013
Total Cost
$435,222
Indirect Cost
$58,754
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Bailey, Shannon T; Westerling, Thomas; Brown, Myles (2015) Loss of estrogen-regulated microRNA expression increases HER2 signaling and is prognostic of poor outcome in luminal breast cancer. Cancer Res 75:436-45
Hines, William C; Su, Ying; Kuhn, Irene et al. (2014) Sorting out the FACS: a devil in the details. Cell Rep 6:779-81
Yamamoto, Shoji; Wu, Zhenhua; Russnes, Hege G et al. (2014) JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 25:762-77
Jeselsohn, Rinath; Yelensky, Roman; Buchwalter, Gilles et al. (2014) Emergence of constitutively active estrogen receptor-? mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 20:1757-67
Lu, Haihui; Clauser, Karl R; Tam, Wai Leong et al. (2014) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16:1105-17
Pathania, Shailja; Bade, Sangeeta; Le Guillou, Morwenna et al. (2014) BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat Commun 5:5496
Hu, Yiduo; Petit, Sarah A; Ficarro, Scott B et al. (2014) PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. Cancer Discov 4:1430-47
McAllister, Sandra S; Weinberg, Robert A (2014) The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 16:717-27
Hill, Sarah J; Rolland, Thomas; Adelmant, Guillaume et al. (2014) Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev 28:1957-75
Hill, Sarah J; Clark, Allison P; Silver, Daniel P et al. (2014) BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol 34:3828-42

Showing the most recent 10 out of 89 publications