The overall lifetime risk of ovarian cancer in North America is 1 in 70. Moreover, ovarian cancer is the fifth leading cause of cancer related deaths in females. The incidence increases with age with the majority of the cases becoming evident in peri-menopausal and menopausal women. There is no effective screening technology and up to 75% of women present with advanced stage disease (stages 3 or 4) that typically includes extensive and bulky intra-abdominal tumor. Although treatable, ovarian cancer is seldom cured. Poor survival is largely attributed to the lack of early detection, lack of understanding about the etiology of the disease, and the development of chemoresistant tumors.
While there are a number of proposed mechanisms by which ovarian epithelial cells transform, relatively little is known about the etiology of ovarian cancer at the cellular and molecular levels. Despite the uncertainties, it is commonly accepted that a majority of the ovarian tumors can be attributed to excessive gonadotropin production, irregular steroid production (i.e. estrogen), germ cell depletion, genetics, mutations in oncogenes (i.e. KRAS, ERBB2, MYC) and/or tumor suppressor genes (BRCA1 and BRCA2, TP53, PTEN) or overproduction of growth factors and/or cytokines.
Rac1 and cancer: It has been demonstrated that overexpression of members of the Ras super-family of GTPases plays a role in the genesis of many cancers. The Rho family constitutes a subgroup of the Ras superfamily of small GTPases. In humans, the Rho family comprises 20 members that regulate a large variety of different functions, including the organization of the actin cytoskeleton, cell migration, mitogenesis and cell survival. Of relevance to this proposal is the work from a number of laboratories showing that the Rho family members Rac, Cdc42 and Rho are essential for cell transformation, tumor cell invasion, and metastasis. Because of their critical role in human oncogenesis the Rho GTPases are attractive targets for anticancer therapies.
The incidence of Rac isoforms in ovarian cancers and their impact in ovarian cancer development and progression have not been studied. To determine whether Rac1b is expressed in ovarian cancers we analyzed thirty two samples from patients with serous ovarian carcinoma, the most common form of ovarian cancer. We found that greater than 55% of the tumor samples express the Rac1b splice variant. Clinical correlates indicated that the presence of Rac1b may predict lack of remission and decreased survival supporting the idea that Rac1b contributes to a more aggressive phenotype. Our research will examine the following aims:
Aim 1: Determine the incidence of Rac isoform expression in ovarian cancer samples and correlate Rac isoform expression to patient outcome (disease recurrence, death) using comprehensive clinical follow-up data for each patient.
Aim 2: Determine the role of Rac1b in ovarian cancer. We intend to answer the questions:
- Does Rac1b contribute to the transformation and invasive properties of ovarian epithelial cells?
- Does Rac1b contribute to tumor development and metastasis?
Aim 3: Determine the sensitivity of ovarian cancer cells to standard therapy with and without Rac1 inhibitors.