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.

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National Cancer Institute (NCI)
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Whitehead Institute for Biomedical Research
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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
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
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

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