JHIBRG:Abstract June 21 2007
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Ovarian cancer pathogenesis: endocrine factors and molecular genetic changes
Ovarian cancer is the sixth most common cancer and the fifth leading cause of cancer-related death among women in developed countries. The pathophysiology of ovarian cancer is the least understood among all major human malignancies due to a poor understanding of the etiological factors and mechanisms of ovarian cancer progression. A growing body of evidence indicates that several key reproductive hormones can influence the incidence and/or growth characteristics of ovarian cancer. These findings are in line with the hormonal carcinogenesis hypothesis suggesting that the endocrine factors that control the normal growth of target organs can also provide suitable conditions for neoplastic transformation. Unlike external risk factors such as diet and smoking, endogenous hormone levels are not easily modified; thus, it is important to understand the molecular changes induced by endocrine factors that might have a positive or negative association with neoplastic transformation in ovarian cancer. In the present study, we will first discuss the supporting evidence and controversies in the “gonadotropin theory”, a long-lived hormonal carcinogenesis theory for ovarian cancer etiology. Tumorigenesis is thought to result, at least in part, from genetic abnormalities that lead to the disruption or enhancement of intracellular signaling pathways that control cell proliferation, apoptosis, or metastasis. Gene amplification is a common mechanism underlying oncogenic activation in human cancer. In ovarian cancer, amplifications of cycline E1, Her2/neu, AKT2 and L-Myc have been reported, and it is expected that additional oncogenic amplifications remain to be identified. We have recently identified two novel amplicons, Rsf-1 and Notch-3, at chromosome 11q13.5 and 19p13.12, respectively in high-grade serous carcinomas through genome wide analysis including digital karyotyping and SNP array. We have previously shown that both genes play a critical role in cell proliferation in ovarian cancer. However, it remains unclear how Rsf-1 upregulation contributes to tumor progression and which Notch ligand interacts with Notch3 and initiates signal transduction in ovarian cancer. In the present study, we found that Jagged-1 is the main ligand for Notch3 signaling in ovarian cancer. In addition, it has been demonstrated that interaction between Rsf-1 and hSNF2H and p53 mutations are required for tumor-promoting fuctions of Rsf-1. Elucidating the molecular mechanisms how amplified genes maintain malignant phenotypes and propel tumor progression is fundamental to understand the molecular etiology of ovarian cancer and would have therapeutic implications.