This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Behbakht, K. Articles by Ford, H. L. Search for Related Content PubMed PubMed Citation Articles by Behbakht, K. Articles by Ford, H. L.

Six1 Overexpression in Ovarian Carcinoma Causes Resistance to TRAIL-Mediated Apoptosis and Is Associated with Poor Survival

Divisions of ¹ Basic Reproductive Sciences and ² Gynecologic Oncology in the Department of Obstetrics and Gynecology and Departments of ³ Pharmacology and ⁴ Biochemistry and Molecular Genetics, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado

Requests for reprints: Kian Behbakht or Heide L. Ford, Department of Obstetrics and Gynecology, Division of Basic Reproductive Sciences, Mail stop 8309, 12800 East 19th Avenue, P.O. Box 6511, Aurora, CO 80045. Phone: 303-724-3522; Fax: 303-724-3512; E-mail: kian.behbakht{at}uchsc.edu or heide.ford{at}uchsc.edu.

Tumorigenesis can arise from inappropriate activation of developmental genes in mature tissues. Here, we show that the developmental regulator Six1 is overexpressed in ovarian carcinoma cell lines (OCC) compared with normal ovarian surface epithelium. As observed in other cancers, Six1 overexpression in OCC leads to increased A-type cyclin expression and increased proliferation. In addition, Six1 overexpression renders OCC resistant to tumor necrosis factor–related apoptosis inducing ligand (TRAIL)–mediated apoptosis, and Six1 knockdown in the TRAIL-resistant SKOV3 ovarian carcinoma line dramatically sensitizes the cells to TRAIL. Because inactivation of the TRAIL response has been linked to metastasis, and because antibodies and recombinant ligand that activate the TRAIL pathway are currently in clinical trials against ovarian carcinoma, we screened normal ovarian and carcinoma specimens for Six1 mRNA. Six1 was overexpressed in 50% of the early-stage (stage I) and 63% of the late-stage (stages II, III, and IV) ovarian carcinomas examined, with late-stage carcinomas expressing 3-fold higher Six1 mRNA levels on average compared with early-stage tumors. Importantly, in patients with late-stage disease, high Six1 expression was associated with significantly shortened survival (P = 0.0015). These data suggest that Six1 may contribute to ovarian epithelial carcinogenesis by simultaneously increasing proliferation and decreasing TRAIL-mediated apoptosis and imply that Six1 may be an important determinant of TRAIL therapy response that should be considered in patient selection for TRAIL-related clinical trials. [Cancer Res 2007;67(7):3036–42]

This article has been cited by other articles:

				R. D. Coletta, K. L. Christensen, D. S. Micalizzi, P. Jedlicka, M. Varella-Garcia, and H. L. Ford Six1 Overexpression in Mammary Cells Induces Genomic Instability and Is Sufficient for Malignant Transformation Cancer Res., April 1, 2008; 68(7): 2204 - 2213. [Abstract] [Full Text] [PDF]