Diseases of the Reproductive System
(T203) FORKHEAD TRANSCRIPTION FACTOR GENE EXPRESSION AND OVARIAN CANCER.
Woad, Kathryn1, Ramachandran, Anassuya1, Shelling, Andrew1, 1 University of Auckland, Auckland, New Zealand
ABSTRACT- Ovarian cancer is the most common cause of death from gynaecologic malignancies. It is often asymptomatic, diagnosed at a late stage and hence characterised by poor survival rates. Members of the forkhead transcription factor or FOX family have been implicated in the regulation of diverse cellular pathways and tumourigenesis. Several FOX genes have been identified as important mediators of follicular growth and function. In addition, a number of FOX genes have been shown to induce apoptotic cell death, and FOX inactivation may, therefore, contribute to both cancer initiation and progression by promoting cell growth and survival. We have investigated the expression of FOX genes in a range of ovarian cancer cell lines of epithelial and granulosa cell origin. The expression levels of the identified FOX genes were quantitated using real time RT-PCR and compared to expression in human normal ovary total RNA. The expression of mRNA encoding FOXO1, FOXO3, FOXA1, FOXC1, and FOXL2 was detected in ovarian cancer cell lines. FOXO1 and -O3 expression was reduced in all 17 cell lines in comparison to normal ovary. Foxo1 has been previously localized to granulosa cells of rodent and porcine ovaries. In this study reduced expression was observed in all cell lines, including those of granulosa cell origin. Downstream targets of FOXO1 and -O3 include proapoptotic Bim, Fas ligand, and TRAIL, and the cyclin dependant kinase inhibitor p27Kip1. Expression of p27Kip1 mRNA was co-ordinately reduced in 16/17 cell lines. Ovarian cancer was also associated with reduced expression of FOXL2 (17/17) and FOXP1 (17/17) mRNA. FOXL2 is an important regulator of granulosa cell differentiation, and FOXL2 mutations are associated with premature ovarian failure. Ovarian functions of FOXP1 are unknown, however, FOXP1 expression is frequently altered in a range of tumours. Variable FOXC1 expression was observed in ovarian cell lines, with observed levels both less than, and greater than levels in normal ovary. FOXA1 mRNA expression was elevated in a number of cell lines (8/17) with levels 2 to 25 times that of normal ovary. Regulation of FOX genes at the level of mRNA expression may prove an important mechanism in the establishment and growth of ovarian cancers, and may provide new opportunities for prognostic indicators and therapeutic intervention.
KEY WORDS: ovary, forkhead, cancer