Breast cancer is associated with the loss of function of tumor suppressor proteins as well as the activation of oncogenes. About 4 percent of all breast cancer cases are associated with the inheritance of mutations at the BRCA1 gene. The BRCA1 gene carries mutations in over half of the cases among families with increased occurrence of breast and/or ovarian cancer. Among sporadic cases of breast cancer, expression of BRCA1 is reduced or undetectable in high grade ductal carcinomas, suggesting that this is a critical tumor suppressor in the etiology of breast cancer. Research in a number of laboratories has indicated that BRCA1 functions in a number of pathways, and our experiments have identified at least three separate protein complexes with which BRCA1 associates. This project will identify components of the three, or more, BRCA1-containing protein complexes, identify domains in BRCA1 which are critical for association with these complexes, and identify domains which are critical for BRCA1 function in transcription, DNA repair, and growth suppression. In this way, these experiments will correlate BRCA1 protein domains to protein complexes and to functional effects. Since BRCA1 is a multifunctional protein, it is critical to dissect the protein domains required for each function. Such structure-function evaluation can then be applied into identifying the key tumor suppressor activity (activities) of BRCA1. This project will clarify key factors in the function of BRCA1 as a tumor suppressor, and it will shed light on the breast and ovarian specificity of BRCA1 mutation.
| Lamber, Ekaterina P; Horwitz, Andrew A; Parvin, Jeffrey D (2010) BRCA1 represses amphiregulin gene expression. Cancer Res 70:996-1005 |
| Ransburgh, Derek J R; Chiba, Natsuko; Ishioka, Chikashi et al. (2010) Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination. Cancer Res 70:988-95 |
| Heine, George F; Horwitz, Andrew A; Parvin, Jeffrey D (2008) Multiple mechanisms contribute to inhibit transcription in response to DNA damage. J Biol Chem 283:9555-61 |
| Pujana, Miguel Angel; Han, Jing-Dong J; Starita, Lea M et al. (2007) Network modeling links breast cancer susceptibility and centrosome dysfunction. Nat Genet 39:1338-49 |
| Horwitz, Andrew A; Affar, El Bachir; Heine, George F et al. (2007) A mechanism for transcriptional repression dependent on the BRCA1 E3 ubiquitin ligase. Proc Natl Acad Sci U S A 104:6614-9 |
| Horwitz, Andrew A; Sankaran, Satish; Parvin, Jeffrey D (2006) Direct stimulation of transcription initiation by BRCA1 requires both its amino and carboxyl termini. J Biol Chem 281:8317-20 |
| Simons, Amanda M; Horwitz, Andrew A; Starita, Lea M et al. (2006) BRCA1 DNA-binding activity is stimulated by BARD1. Cancer Res 66:2012-8 |
| Ko, M J; Murata, K; Hwang, D-S et al. (2006) Inhibition of BRCA1 in breast cell lines causes the centrosome duplication cycle to be disconnected from the cell cycle. Oncogene 25:298-303 |
| Sankaran, Satish; Starita, Lea M; Simons, Amanda M et al. (2006) Identification of domains of BRCA1 critical for the ubiquitin-dependent inhibition of centrosome function. Cancer Res 66:4100-7 |
| Starita, Lea M; Horwitz, Andrew A; Keogh, Michael-Christopher et al. (2005) BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II. J Biol Chem 280:24498-505 |
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