Decreased Expression of the Early Mitotic Gene, CHFR, Contributes to the Acquisition of Breast Cancer Phenotypes
Annual rept. 6 Feb 2007-5 Feb 2008
MICHIGAN UNIV ANN ARBOR
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CHFR is an E3 ubiquitin ligase that reportedly delays mitosis in response to microtubule-targeting drugs i.e. nocodazole and taxanes. Loss of CHFR mRNA expression has been reported in many cancers, including breast cancer, but the relevance of this to tumorigenesis remains unknown. The purpose of this study was to determine if CHFR was biologically relevant to breast cancer characteristics, progression, and genomic stability. As previously reported, nearly 40 of breast cancer show decreased CHFR expression compared to normal cells and tissues and the loss of CHFR expression by RNAi in cell culture models leads to the acquisition of several tumorigenic phenotypes. In particular, MCF10A IHMEC cells transfected with CHFR siRNA, became aneuploid and were analyzed for chromosome segregation defects. We observed increased aneuploidy, misaligned metaphase chromosomes, anaphase bridges, multipolar condensed spindles, multi-nucleated cells, and mislocalization of the mitotic spindle checkpoint proteins MAD2 and BUBR1. CHFR was found to interact with three crucial mitosis proteins, including MAD2 and Aurora A where CHFR loss led to Aurora A oncoprotein over-expression, but no change in MAD2 expression. alpha-tubulin was identified as a novel target for CHFR-mediated ubiquitination after nocodazole treatment and decreased CHFR increased acetylated alpha-tubulin, a mitotic spindle protein implicated in cellular response to taxane treatment. These data indicate that CHFR has tumor suppressive qualities and may be a biomarker for taxane chemo-responsiveness. CHFR also has a previously unrecognized role as a regulator of genomic stability. CHFR may be one of the few proteins that can control the cell cycle, chemotherapeutic response, and genomic stability - processes that go awry in breast cancer.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research