TGFSignaling in Ovarian Cancer

Ovarian cancer is one of the most lethal gynecological cancers in the United States. NCI estimates ~21,880 new cases with ~13,850 deaths in 2011 (http://www.cancer.gov/ cancertopics/ types/ovariancancer). Unfortunately, the majority of these cases are only discovered at advanced stages (stage III or IV) due to the cancer’s asymptomatic nature which has an overall survival rate between 5-25% (Bast et al., 2009; Hennessy et al., 2008). Hence, the inability to detect this disease during early stages has led to poor prognosis. Despite improvements in medicine and patient care, reasonable screening measures for detecting early stage ovarian cancers are presently lacking. Thus, a better understanding of the molecular events that underlie ovarian cancer development are needed. The current strategy for treatment of ovarian cancer is surgical debulking followed by chemotherapy (Bast et al., 2009; Hennessy et al., 2008). Although ~70% of ovarian cancers respond to a combination of platinum and taxane-based chemotherapy administered after surgery, current treatments are of limited efficacy in preventing tumor recurrence and progression (Bast et al., 2009; Hennessy et al., 2008). Thus, new anti-neoplastic agents are urgently needed to increase the chemotherapeutic sensitivity of ovarian cancer cells. Recently, evidence has emerged revealing the importance of genomic aberrations in the progression of ovarian cancer (Gorringe & Campbell, 2009; Gray et al., 2003). Through the use of high throughput technologies (i.e. array comparative genomic hybridization (aCGH), microarray, and SNP arrays), specific genomic regions have been identified to be either amplified or silenced in tumor progression (Gorringe & Campbell, 2009; Gray et al., 2003). One such region which we and others (Nanjundan et al., 2007; Osterberg et al., 2009) have previously identified to be frequently amplified early in serous epithelial ovarian cancer development is the 3q26.2 region which harbors Transforming Growth Factor  pathway (TGF) co-repressors, ecotropic viral integration site-1 (EVI1) (Nanjundan et al., 2007) and SnoN/SkiL (Nanjundan et al., 2008). A large amount of work has recently emerged involving the intricacies of TGF signaling and its role in cancer progression. Importantly, this signaling pathway is dysregulated in ovarian carcinomas.