The oncogene RAS is known to induce genomic instability, leading to cancer development; the underlying mechanism, however, remains poorly understood. To better understand how RAS functions, we measured the activity of the functionally related genes Aurora-A and BRCA2 in ovarian cancer cell lines and tumor samples containing RAS mutations. We found that Aurora-A and BRCA2 inversely controlled RAS-associated genomic instability and ovarian tumorigenesis through regulation of cytokinesis and polyploidization. Overexpression of mutated RAS ablated BRCA2 expression but induced Aurora-A accumulation at the midbody, leading to abnormal cytokinesis and ultimately chromosomal instability via polyploidy in cancer cells. RAS regulates the expression of Aurora-A and BRCA2 through dysregulated protein expression of farnesyl protein transferase and insulin-like growth factor binding protein 3. Our results suggest that the imbalance in expression of Aurora-A and BRCA2 regulates RAS-induced genomic instability and tumorigenesis.
[1]Fudan Univ, Shanghai Canc Ctr, Canc Res Lab, Shanghai 200032, Peoples R China.
[2]Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China.
[3]Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA.
[4]Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA.
[5]Univ Texas MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA.
[6]Johns Hopkins Univ, Sch Med, Dept Gynecol Pathol, Baltimore, MD USA.
[7]Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA.
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