5742

Background: The STK15 (also known as Aurora-A/BTAK) gene localized on chromosome 20q13 and encoding a centrosome-associated serine/threonine kinase, is amplified and overexpressed in multiple human tumor-cell types. Over expression of this gene is involved in tumorigenic transformation, induction of centrosome duplication-distribution abnormalities, and aneuploidy in mammalian cells. Methods: To examine the potential role of STK15 in ovarian tumorigenesis, its mRNA and protein expression status were examined in cells grown in culture from 15 ovarian cancer specimens using semi-quantitative RT-PCR and Western blot analysis. Normal ovarian surface tissues and the near diploid non-tumorigenic breast epithelial cell line MCF10 were used as controls. The status of STK15 correlated with transformation associated cellular phenotypes including tumorigenicity in nude mice, p53 expression level and chromosomal ploidy. For chromosome ploidy analyses, FISH was carried out with direct fluorescence-labeled α-satellite probes for chromosome 3 and 17. Results: STK15 mRNA was found over expressed in 10 of the 15 ovarian cancer cell cultures. Five of these cell cultures revealed a truncated form of the STK15 protein with a molecular mass of 36 kDa. When tested for tumorigenicity in nude mice, nine of the ten cell cultures that over expressed STK15 mRNA formed tumors in nude mice, while only one of the five cell cultures with no over-expression did. Cells over expressing STK15 mRNA showed significant correlation with chromosome 3 polysomy. Six of the 13 (46%) cell cultures analyzed for p53 expression revealed over expression of p53 and five of these six (83%) also overexpressed STK15. Four of the remaining seven cultures (57%), with over expression of STK15, revealed minimal or no expression of P53. Conclusions: These results demonstrate that overexpression of STK15 significantly correlates with nude mice tumorigenicity and chromosomal aneuploidy in human ovarian cancer cells grown in vitro. Additionally, cells overexpressing STK15 also revealed frequent coordinate loss of wild type p53 function manifested either as highly expressed intense staining reflective of a mutant form of p53 or almost complete absence of p53 staining. Overexpression of STK15 with coordinate loss of wild type p53 function thus appears to play an important role in ovarian tumorigenesis and offers a novel molecular target in designing effective therapy of human ovarian cancer.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]