Perturbation of Rb, p53, and Brca1 or Brca2 Cooperate in Inducing Metastatic Serous Epithelial Ovarian Cancer

Center for Advanced Preclinical Research, Advanced Biomedical Computing Center, SAIC at Frederick National Laboratory for Cancer Research, Mouse Cancer Genetics Program, NCI-Frederick, Frederick, Maryland 21702, USA.
Cancer Research (Impact Factor: 9.33). 05/2012; 72(16):4141-53. DOI: 10.1158/0008-5472.CAN-11-3834
Source: PubMed


The majority of human high-grade serous epithelial ovarian cancer (SEOC) is characterized by frequent mutations in p53 and alterations in the RB and FOXM1 pathways. A subset of human SEOC harbors a combination of germline and somatic mutations as well as epigenetic dysfunction for BRCA1/2. Using Cre-conditional alleles and intrabursal induction by Cre-expressing adenovirus in genetically engineered mice, we analyzed the roles of pathway perturbations in epithelial ovarian cancer initiation and progression. Inactivation of RB-mediated tumor suppression induced surface epithelial proliferation with progression to stage I carcinoma. Additional biallelic inactivation and/or missense p53 mutation in the presence or absence of Brca1/2 caused progression to stage IV disease. As in human SEOC, mice developed peritoneal carcinomatosis, ascites, and distant metastases. Unbiased gene expression and metabolomic profiling confirmed that Rb, p53, and Brca1/2-triple mutant tumors aligned with human SEOC, and not with other intraperitoneal cancers. Together, our findings provide a novel resource for evaluating disease etiology and biomarkers, therapeutic evaluation, and improved imaging strategies in epithelial ovarian cancer.

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    • "Extensive analyses of human ovarian cancer specimens have identified several genetic alterations associated with malignancy including TP53, C-MYC, K-RAS, AKT, and BRCA1 and BRCA2 (36–38). Subsequently, several genetically modified ovarian cancer models, summarized in Table 1, have been developed to explore the contribution of these different aberrations to ovarian cancer development (39–44). "
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    ABSTRACT: Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered mice, have been developed to provide a mechanism for studying the development and progression of SEOC. Such models strive to increase our understanding of the etiology and dissemination of ovarian cancer in order to overcome barriers to early detection and resistance to standard chemotherapy. Although there is not a single model that is most suitable for studying ovarian cancer, improvements have led to current models that more closely mimic human disease in their genotype and phenotype. Other advances in the field, such as live animal imaging techniques, allow effective monitoring of the microenvironment and therapeutic efficacy. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly render success of future human clinical trials for patients with SEOC.
    Frontiers in Oncology 02/2014; 4:26. DOI:10.3389/fonc.2014.00026
    • "Of particular interest appears the involvement of AHR, CHK1, and Plks, as several drugs that target these molecules are currently available (Ganguly and Shields, 2010). In addition, using genetically engineered mice, it has been shown (Szabova et al., 2012), that inactivation of RB1 induces surface epithelial proliferation with progression to stage I carcinoma, and that additional biallelic inactivation and/or missense TP53 mutation in the presence or absence of BRCA1/2 cause progression to stage IV disease. Moreover, as in human serous epithelial ovarian cancer, mice developed peritoneal carcinomatosis, ascites, and distant metastases. "
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    ABSTRACT: Loss of RB1 gene is considered either a causal or an accelerating event in retinoblastoma. A variety of mechanisms inactivates RB1 gene, including intragenic mutations, loss of expression by methylation and chromosomal deletions, with effects which are species- and cell type- specific. RB1 deletion can even lead to aneuploidy thus greatly increasing cancer risk. The RB1gene is part of a larger gene family that includes RBL1 and RBL2, each of the three encoding structurally related proteins indicated as pRb, p107 and p130, respectively. The great interest in these genes and proteins springs from their ability to slow down neoplastic growth. pRb can associate with various proteins by which it can regulate a great number of cellular activities. In particular, its association with the E2F transcription factor family allows the control of the main pRb functions, while the loss of these interactions greatly enhances cancer development. As RB1 gene, also pRb can be functionally inactivated through disparate mechanisms which are often tissue specific and dependent on the scenario of the involved tumor suppressors and oncogenes. The critical role of the context is complicated by the different functions played by the RB proteins and the E2F family members. In this review, we want to emphasize the importance of the mechanisms of RB1/pRb inactivation in inducing cancer cell development. The review is divided in three chapters describing in succession the mechanisms of RB1 inactivation in cancer cells, the alterations of pRb pathway in tumorigenesis and the RB protein and E2F family in cancer. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 08/2013; 228(8). DOI:10.1002/jcp.24329 · 3.84 Impact Factor
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    • "In contrast to the previous reports [66,67], inactivation of RB1 (and p107, p130) following activation of the T121 led to a range of abnormalities in the OSE including serous EOC (often high grade) in 18% of mice. Single or double loss of Trp53, Brca1 or Brca2 function failed to generate OSE pathology while loss of p53 alleles in conjunction with expression of T121 led to both the increased frequency and progression of high grade serous EOC [70]. "
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    ABSTRACT: The development of genetically engineered models (GEM) of epithelial ovarian cancer (EOC) has been very successful, with well validated models representing high grade and low grade serous adenocarcinomas and endometrioid carcinoma (EC). Most of these models were developed using technologies intended to target the ovarian surface epithelium (OSE), the cell type long believed to be the origin of EOC. More recent evidence has highlighted what is likely a more prevalent role of the secretory cell of the fallopian tube in the ontogeny of EOC, however none of the GEM of EOC have demonstrated successful targeting of this important cell type. The precise technologies exploited to develop the existing GEM of EOC are varied and carry with them advantages and disadvantages. The use of tissue specific promoters to model disease has been very successful, but the lack of any truly specific OSE or oviductal secretory cell promoters makes the outcomes of these models quite unpredictable. Effecting genetic change by the administration of adenoviral vectors expressing Cre recombinase may alleviate the perceived need for tissue specific promoters, however the efficiencies of infection of different cell types is subject to numerous biological parameters that may lead to preferential targeting of certain cell populations. One important future avenue of GEM of EOC is the evaluation of the role of genetic modifiers. We have found that genetic background can lead to contrasting phenotypes in one model of ovarian cancer, and data from other laboratories have also hinted that the exact genetic background of the model may influence the resulting phenotype. The different genetic backgrounds may modify the biology of the tumors in a manner that will be relevant to human disease, but they may also be modifying parameters which impact the response of the host to the technologies employed to develop the model.
    Journal of Ovarian Research 11/2012; 5(1):39. DOI:10.1186/1757-2215-5-39 · 2.43 Impact Factor
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