Dinulescu, D.M. et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat. Med. 11, 63-70

Center for Cancer Research, Massachusetts Institute of Technology, 40 Ames Street, Cambridge, Massachusetts 02139, USA.
Nature Medicine (Impact Factor: 27.36). 02/2005; 11(1):63-70. DOI: 10.1038/nm1173
Source: PubMed


Epithelial ovarian tumors present a complex clinical, diagnostic and therapeutic challenge because of the difficulty of early detection, lack of known precursor lesions and high mortality rates. Endometrioid ovarian carcinomas are frequently associated with endometriosis, but the mechanism for this association remains unknown. Here we present the first genetic models of peritoneal endometriosis and endometrioid ovarian adenocarcinoma in mice, both based on the activation of an oncogenic K-ras allele. In addition, we find that expression of oncogenic K-ras or conditional Pten deletion within the ovarian surface epithelium gives rise to preneoplastic ovarian lesions with an endometrioid glandular morphology. Furthermore, the combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas with complete penetrance and a disease latency of only 7 weeks. The ovarian cancer model described in this study recapitulates the specific tumor histomorphology and metastatic potential of the human disease.

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    • "Existing mouse models for serous extra-uterine Müllerian (previously referred to as serous ovarian) carcinomas (Dubeau, 2008; Dubeau and Drapkin, 2013), are based on forced expression of selected oncogenes, often combined with homozygous knockouts of BRCA1 or BRCA2 or other relevant tumor suppressor genes in a tissue-specific manner (Miyoshi et al., 2002; Orsulic et al., 2002; Connolly et al., 2003; Flesken-Nikitin et al., 2003; Dinulescu et al., 2005; Clark-Knowles et al., 2007; Szabova et al., 2012; Perets et al., 2013). None of these models, to our knowledge, are associated with predisposition to both reproductive and mammary cancers. "
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    ABSTRACT: Predisposition to breast and extrauterine Müllerian carcinomas in BRCA1 mutation carriers is due to a combination of cell-autonomous consequences of BRCA1 inactivation on cell cycle homeostasis superimposed on cell-nonautonomous hormonal factors magnified by the effects of BRCA1 mutations on hormonal changes associated with the menstrual cycle. We used the Müllerian inhibiting substance type 2 receptor (Mis2r) promoter and a truncated form of the Follicle stimulating hormone receptor (Fshr) promoter to introduce conditional knockouts of Brca1 and p53 not only in mouse mammary and Müllerian epithelia, but also in organs that control the estrous cycle. Sixty percent of the double mutant mice developed invasive Müllerian and mammary carcinomas. Mice carrying heterozygous mutations in Brca1 and p53 also developed invasive tumors, albeit at a lesser (30%) rate, in which the wild type alleles were no longer present due to loss of heterozygosity. While mice carrying heterozygous mutations in both genes developed mammary tumors, none of the mice carrying only a heterozygous p53 mutation developed such tumors (P<0.0001), attesting to a role for Brca1 mutations in tumor development. This mouse model is attractive to investigate cell-nonautonomous mechanisms associated with cancer predisposition in BRCA1 mutation carriers and to investigate the merit of chemo-preventive drugs targeting such mechanisms.
    09/2015; DOI:10.1016/j.ebiom.2015.08.034
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    • "The fact of metaplasia of undifferentiated tissue could possibly explain the existence of endometriosis in distant sites. Dinelescu et al. came up with the hypothesis that activation of K-ras gene may be responsible for the metaplastic process [2] . "

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    • "To explore the tumorigenic contributions of oncogenic Kras and tumor suppressor Pten pathways throughout the female genital tract of genetically engineered, Cre-loxP mice [21], [26], we injected AdCre adenovirus at three different anatomical locations (Fig. 1A). The mice received one, unilateral AdCre injection either in the ovarian bursa (n = 12), oviduct (the fallopian tube equivalent, n = 9) or uterine horn (n = 12). "
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    ABSTRACT: Activating mutations of Kras oncogene and deletions of Pten tumor suppressor gene play important roles in cancers of the female genital tract. We developed here new preclinical models for gynecologic cancers, using conditional (Cre-loxP) mice with floxed genetic alterations in Kras and Pten. The triple transgenic mice, briefly called MUC1KrasPten, express human MUC1 antigen as self and carry a silent oncogenic KrasG12D and Pten deletion mutation. Injection of Cre-encoding adenovirus (AdCre) in the ovarian bursa, oviduct or uterus activates the floxed mutations and initiates ovarian, oviductal, and endometrial cancer, respectively. Anatomical site-specific Cre-loxP recombination throughout the genital tract of MUC1KrasPten mice leads to MUC1 positive genital tract tumors, and the development of these tumors is influenced by the anatomical environment. Endometrioid histology was consistently displayed in all tumors of the murine genital tract (ovaries, oviducts, and uterus). Tumors showed increased expression of MUC1 glycoprotein and triggered de novo antibodies in tumor bearing hosts, mimicking the immunobiology seen in patients. In contrast to the ovarian and endometrial tumors, oviductal tumors showed higher nuclear grade. Survival for oviduct tumors was significantly lower than for endometrial tumors (p = 0.0015), yet similar to survival for ovarian cancer. Oviducts seem to favor the development of high grade tumors, providing preclinical evidence in support of the postulated role of fallopian tubes as the originating site for high grade human ovarian tumors.
    PLoS ONE 07/2014; 9(7):e102409. DOI:10.1371/journal.pone.0102409 · 3.23 Impact Factor
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