Human breast tumors typically display high levels of chromosomal rearrangements, most of which harbor sequence microhomologies (MH) at their junctions. The presence of these MHs suggests that tumor associated chromosome aberrations may arise when double-strand DNA breaks (DSBs) are repaired illegitimately by microhomology-mediated end-joining (MMEJ) rather than preferred modes of DSB repair, such as non-homologous end-joining (NHEJ) or homology-directed repair (HDR). This intriguing idea is supported by recent evidence that the CtlP protein, a key mediator of DNA resection, is essential for MMEJ, and that CtIP inactivation markedly suppresses the formation of chromosome translocations. Woman with germline mutations ofthe BRCA1 tumor suppressor gene often develop basal-like breast carcinoma, an especially lethal subtype of human breast cancer characterized by extensive chromosomal instability. Previously, we reported that the BRCT repeats of the BRCAI polypeptide interact with CtIP and that this interaction is ablated by tumorigenic BRCA1 missense mutations. Subsequently, we used conditional mutagenesis to show that basal-like breast tumors can be induced in mice by mammary-specific Brca1inactivation and that the BRCT repeats are essential for both the chromosome stability and tumor suppression functions of BRCAI. To ascertain whether CtIP also contributes to tumor suppression, we recently examined the effects of mammary-specific Ctip inactivation in mice. Remarkably, Ctip ablation strongly suppressed breast cancer formation in p53-deficient animals. By providing the first experimental evidence that Ctip can promote tumorigenesis, this result is consistent with the central hypothesis of this Program;that DSB repair by CtlP-dependent MMEJ can lead to oncogenic chromosomal rearrangements. Therefore, to explore this hypothesis. Project 4 will determine 1) how CtIP facilitates breast cancer development, 2) whether CtIP is required for development of basal-like breast cancer, and 3) whether Ctip is involved in Myc-driven breast cancer.
Aberrant chromosomal rearrangements are implicated in most human malignancies, including breast cancer. Our preliminary data show that depletion of CtlP, a DNA repair protein that promotes the formation of chromosome translocations, dramatically reduces breast tumor development in mice. By defining how Ctip promotes chromosomal rearrangements and breast carcinogenesis, the proposed project should identify valuable molecular targets and new strategies for cancer prevention and therapy.
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