Functional Interactions of the TACC2 Breast Tumor Suppressor Gene and Its Relevance to Breast Tumor Progression

摘要

Previous analyses suggested that loss of the transforming acidic coiled coil gene 2 (TACC2) occurs during breast tumorigenesis. TACC2 induced inhibition of the tumorigenic phenotype of certain breast cancer cells is mediated via the conserved TACC domain. This region binds to the histone acetyltransferases (HATs), hGCN5, and pCAF. We have now shown that hGCN5 is also downregulated in breast cancer, and that introduction of hGCN5 into cell lines can inhibit cellular division. Significantly, TACC2 can negate the in vitro suppression of DNA-dependent protein kinase (DNA-PK) mediated pCAF activity. This suggests that defects in TACC2 may impact chromatin structure, DNA repair and gene transcription Thus, we have begun to address the potential interface between TACC2 and BRCA1 mediated regulation of the p21 gene. Our initial data suggests that basal levels of p2l and STAT1 are decreased in TACC2 transfected cell lines, resulting in defective p2l induction by interferon gamma. TACC2 does not directly bind BRCA1, but may compete with BRCA1 in a ternary complex with FHL2, a promoter specific coregulator. Combined, the data generated in this proposal indicates an intimate role of TACC2 at multiple levels in cell signaling pathways regulating mammary gland development and tumorigenesis.