Do Deregulated Cas Proteins Induce Genomic Instability in Early-Stage Ovarian Cancer

Increased genomic instability arising from centrosomal amplification has been proposed to be an important factor causing development of traits associated with highly malignant ovarian tumors, including multidrug resistance and increased tendency to metastasis. This proposal addresses the hypothesized interaction between the Cas proteins HEF1 and p130Cas, Aurora A AurA and Ajuba as being likely to contribute to genomic instability and metastatic properties of ovarian tumors. Our work during the no cost extension has begun investigating the association between HEF1 overexpression and AurA activation in primary ovarian tumors, with data suggesting a potential correlation. We have also used mouse models to directly assess the effect of modulating HEF1 on cancer progression, and have data suggesting the absence of HEF1 also predisposes cancers to abnormal mitoses, centrosomal defects, and genomic instability. In the past three years, elevation of HEF1 has been established as important for metastasis andor invasion in lung cancer, melanoma, and glioblastoma, while reduction of HEF1 has been suggested as relevant in metastatic breast cancers our ongoing work will establish the role of HEF1 in ovarian cancer.