We propose strategies to produce inheritable mouse models of ovarian cancer. Such models will aid in understanding the disease's etiology and provide more realistic systems in which to evaluate diagnostic, prevention, and treatment methods. Creation of transgenic ovarian cancer models is a particularly rational goal considering this disease is the fourth leading cause of deaths from solid tumors in American women and transgenic models of the three more commonly lethal solid tumors currently exist. The need for such models is further underscored when one considers the risk of death from ovarian cancer compared to for example breast cancer. The incidence of ovarian cancer is approximately 3.3 per 100,000 women in the United Sates. This yields approximately 20,000 new cases annually but they result in a remarkably high frequency of death, i.e. nearly 15,000 American women die from the disease each year. In contrast, breast cancer has a frequency of approximately 180,000 cases per year and accounts for approximately 46,000 annual deaths. Thus, breast cancer has a frequency 9 times as high as ovarian cancer but results in 3-times as many deaths. In this application, we demonstrate that sufficient resources exist to begin to develop inheritable models of ovarian cancer and describe approaches to obtain the resources and information needed to create second generation models. To accomplish these goals, we propose the following Specific Aims:
SPECIFIC AIM number 1: Identify the genes which when overexpressed, expressed in aberrant form, or inactivated will likely lead to an increased risk of ovarian cancer: Sufficient information is available to start producing transgenic animals with several dominantly acting genes/oncogenes. A much larger problem exists with regard to selection of recessively acting genes, i.e. those genes whose lost function contributes to ovarian oncogenesis. Identification of such genes for manipulation in transgenic animals is the focus of this Aim.
SPECIFIC AIM number 2: Creation of genetically engineered mice at increased risk of developing ovarian cancer. We have identified a retrovirus-like element in the rat genome which is specifically expressed in rat ovaries. We have cloned the portion of it responsible for ovarian specific expression and demonstrated that it drives reporter gene expression. This promoter will serve as the backbone of our initial efforts to develop mouse models of ovarian cancer. In this Aim, we propose to use this promoter to create transgenic mice constitutively expressing normal and mutated genes of importance in ovarian cancer. In the case of recessive genes, i.e. tumor/growth suppresser genes, we have the capability to produce germline """"""""knockouts"""""""", but of greater interest is the possibility of using this promoter to drive ovarian specific intrabody production as a means to functionally """"""""knockout"""""""" tumor/growth suppresser genes in an ovarian specific manner.
SPECIFIC AIM number 3: Identify a promoter that is specifically expressed in MOSE cells. The promoter currently available functions in multiple ovarian cell types including the surface epithelium. Therefore, the ovarian tumors produced when genes are manipulated under control of this promoter may derive from multiple cell types. Such tumor models will be of certain interest although theca and granulosa cell tumors are not as common in women as those derived from the surface epithelium. Here, we propose to identify a mouse ovarian surface epithelial cell specific promoter.
SPECIFIC AIM number 4: Increase carcinoma frequency and specificity and decrease latency. Here, we will examine various genetic and physiological strategies as needed to increase frequency, specificity, and decrease latency of ovarian cancer in mice.
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