Research Article: Induction of Ovarian Leiomyosarcomas in Mice by Conditional Inactivation of Brca1 and p53

Date Published: December 31, 2009

Publisher: Public Library of Science

Author(s): Bridget A. Quinn, Tiffany Brake, Xiang Hua, Kimberly Baxter-Jones, Samuel Litwin, Lora Hedrick Ellenson, Denise C. Connolly, Sudhansu Kumar Dey.

Abstract: Approximately one out of every ten cases of epithelial ovarian cancer (EOC) is inherited. The majority of inherited cases of EOC result from mutations in the breast cancer associated gene 1 (BRCA1). In addition to mutation of BRCA1, mutation of the p53 gene is often found in patients with inherited breast and ovarian cancer syndrome.

Partial Text: Approximately 10% of cases of epithelial ovarian cancer (EOC) are associated with a clear hereditary predisposition to disease; the vast majority of cases resulting from inherited alterations in the breast cancer-associated tumor suppressor genes 1 or 2 (BRCA1 or BRCA2) (reviewed in: [1], [2], [3]). BRCA1 and BRCA2 were originally identified based on genetic linkage to families with an increased risk of breast and ovarian cancer. The proteins encoded by these genes control normal cellular growth by their involvement in DNA damage repair, maintenance of genomic integrity, chromatin remodeling and transcription regulation [4], [5]. Linkage to the BRCA1 gene exists in ∼80% of families with inherited risk of breast and ovarian cancer [1], [2], [3]. Although mutations of the BRCA1 gene are not frequently detected in sporadic cases of EOC, recent studies have suggested that other mechanisms of inactivation of this tumor suppressor gene, such as promoter methylation and mutations in non-coding regions that effect functional protein expression, may exist in sporadic tumors [6], [7], [8], [9], [10]. In addition to alterations in BRCA1 and BRCA2, mutation of the p53 gene is reported in 70–90% of patients with familial breast and ovarian cancer syndrome [11], [12], [13], [14]. Interestingly, p53 mutations are identified more frequently in BRCA1-associated and sporadic serous ovarian carcinomas than in sporadic ovarian cancers of other histologic subtypes [11], [12], [13], [14]. A role for p53 in BRCA1-associated inherited breast and ovarian cancer is further supported by the cooperation of p53 with BRCA1 in the development of mammary tumor development in genetically engineered mouse (GEM) models [15], [16].

Although the lifetime risk of developing ovarian cancer is increased in women with germline mutations of BRCA1, previous studies in mice suggest that loss of Brca1 alone was insufficient to lead to the development of EOC [22], [23], [25]. A number of independent studies [11], [12], [13], [14] have shown that in cases of EOC with BRCA1 mutations, the frequency of mutations of p53 is high, ranging from 70–90%. Moreover, in mouse models of mammary cancer, tumor latency is decreased and incidence of tumor formation increased in mice with both conditional inactivation of Brca1 and a p53 null allele [15]. This apparent cooperation of Brca1 and p53 in inherited breast and ovarian cancer in humans and in mammary tumor development in mice led us to create a mouse model of ovarian cancer by conditional inactivation of Brca1 and p53 in the ovarian epithelium.



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