BRCA1-mediated pathways in genomic stability and tumorigenesis
Qimin Zhan
State Key Laboratory of Molecular Oncology
Cancer Institute, Chinese Academy of Medical Sciences
Beijing, 100021, China

The control of cell cycle progression has been shown to be associated with the maintenance of genomic fidelity. Defects in the regulation of cell cycle progression may result in genomic instabilities, including gene mutation, amplification or chromosomal aberration, which are associated with malignant transformation and tumorigenesis. In addition, the inactivation of cell cycle control can also have dramatic consequences on therapeutic sensitivity.
The essence of successful mitosis in mammalian cells is the generation of two genetically identical daughter cells. The successful mitosis requires the assembly of a strictly bipolar mitotic apparatus that will ensure that chromosomes equally distribute to the daughter cells. This process is controlled by the centrosomes that are required for spindle formation and function. Centrosome stability is required for the successful mitosis in mammalian cells. Amplification of centrosome leads to chromosomal missegregation and generation of aneuploidy, which are closely associated with cell transformation and tumorigenesis. Breast cancer susceptibility gene BRCA1 is implicated in the control of mitotic machinery although there is little insight into underlying mechanism(s). Here, we show that BRCA1 physically interacts and colocalizes with Bacp (BRCA1 associated centrosomal protein). Interestingly, Bacp centrosomal localization likely depends on normal cellular BRCA1 function since cells containing BRCA1 mutations or silenced for endogenous BRCA1 reveal disrupted Bacp colocalization to centrosomes. Suppression of endogenous Bacp results in aberrant spindle formation, failure of chromosomal segregation and cytokinesis, and aneuploidy. Bacp is overexpressed in human breast and lung carcinomas, and its deregulation is in part associated with BACP amplification. Bacp exhibits strong oncogenic property and induces NIH3T3 fibroblasts transformation. Importantly, Bacp transgenic mice mimic the phenotypes of disrupted BRCA1, including centrosome amplification and spontaneous tumorigenesis. Thus, Bacp may cooperatively act together with BRCA1 in mitotic machinery, and abnormalities of Bacp leads to genomic instability and tumorigenesis.