Mutual Contribution of Pten and Estrogen to Endometrial Carcinogenesis in a PtenloxP/loxP Mouse Model

Saito, Fumitaka; Tashiro, Hironori; To, Yoko; Ohtake, Hideyuki; Ohba, Takayoshi; Suzuki, Akira; Katabuchi, Hidetaka

doi:10.1097/igc.0b013e31822d2a8a

Cited by 14 publications

(9 citation statements)

References 21 publications

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“…In our current study, simple hyperplasia was the most advanced epithelial lesion caused by Pten -null mutation, replicating the clinical observations in human patients. Previous studies also demonstrated that Pten -null mutation induced by direct injection of adenovirus Cre into the mouse uterus caused atypical hyperplasia but not gross uterine tumors (10, 49). In contrast, mouse model studies utilizing uterine tissue-specific Cre transgenes (e.g., Pgr-Cre , Ksp-Cre , Sprr2f-Cre ) demonstrated that Pten mutation alone causes large uterine tumors (50–52).…”

Section: Discussionmentioning

confidence: 90%

Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities

Terakawa

Serna

Taketo

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Endometrioid endometrial carcinomas (EECs) carry multiple driver mutations even when they are low grade. However, the biological significance of these concurrent mutations is unknown. We explored the interactions among three signature EEC mutations: loss-of-function (LOF) mutations inPTEN, gain-of-function (GOF) mutations of phosphoinositide 3-kinase (PI3K), andCTNNB1exon 3 mutations, utilizing in vivo mutagenesis of the mouse uterine epithelium. While epithelial cells with a monoallelic mutation in any one of three genes failed to propagate in the endometrium, any combination of two or more mutant alleles promoted the growth of epithelium, causing simple hyperplasia, in a dose-dependent manner. Notably,Ctnnb1exon 3 deletion significantly increased the size of hyperplastic lesions by promoting the growth of PTEN LOF and/or PI3K GOF mutant cells through the activation of neoadenogenesis pathways. Although these three mutations were insufficient to cause EEC in intact female mice, castration triggered malignant transformation, leading to myometrial invasion and serosal metastasis. Treatment of castrated mice with progesterone or estradiol attenuated the neoplastic transformation. This study demonstrates that multiple driver mutations are required for premalignant cells to break the growth-repressing field effect of normal endometrium maintained by ovarian steroids and thatCTNNB1exon 3 mutations play critical roles in the growth of preneoplastic cells within the endometrium of premenopausal women and in the myometrial invasion of EECs in menopausal women.

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Section: Discussionmentioning

confidence: 90%

Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities

Terakawa

Serna

Taketo

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast, Joshi et al showed that Pten-/+ mice developed endometrial carcinoma, whereas the simultaneous knockout of ERα resulted in a higher incidence of endometrial carcinoma, suggesting that endometrial carcinogenesis is independent of estrogen and ERα [23]. Moreover, Saito et al reported that Pten conditional knockout mice in the endometrium using the Cre-loxP system developed endometrial carcinoma; however, the tumor formation was suppressed by the addition of E2 [24]. This discrepancy may be due in part to methodological differences.…”

Section: Discussionmentioning

confidence: 96%

Elevated Serum Levels of Estradiol Induce Endometrial Hyperplasia Rather than Carcinoma in a Mouse Model Using a Carcinogen

Asaka¹,

Miyamoto²,

Yumura³

et al. 2017

J Carcinog Mutagen

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Objective: Although estrogen has been regarded as a risk factor for endometrial carcinoma, its concentrationdependent carcinogenetic effects remain unclear, because most endometrial carcinomas occur in post-menopausal women, whose serum estrogen levels are relatively low. We previously reported that high levels of estradiol (E2) may suppress endometrial carcinogenesis by up-regulating DNA mismatch repair (MMR) in vitro. The present study was undertaken to further examine the carcinogenetic role of estrogen at various concentrations in vivo.Methods: N-methyl-N-nitrosourea (MNU) was injected into the uterine cavity of 29 mice, and E2 was administered by pellets or orally. Uteri were removed for histological examinations 24 weeks later, and serum E2 levels were measured. The immunohistochemical expression of MMR proteins in uterine epithelia was investigated.Results: Of 29 mice, 8, 8, 8, and 5 showed atrophic, normal, hyperplastic, and carcinomatous endometria, respectively. The mean E2 levels of each group were 0.2 pg/ml, 3.8 pg/ml, 190.0 pg/ml, and 6.7 pg/ml, with significant differences. The expression of the MMR proteins was stronger in mice with elevated E2. Conclusion:Elevated E2 levels preferentially induced endometrial hyperplasia rather than carcinoma, and this may be mediated by MMR proteins. These results indicate that modest E2 is needed, whereas elevated E2 levels are not necessarily advantageous for carcinogenesis, suggesting the importance of low-chronic (un-opposed) estrogen in human endometrial carcinogenesis.

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“…While empirical data from our laboratory and others have indicated that adenovirus can infect the epithelium of the ovary, oviduct and uterus [94], it remains a concern that subsets of cells may have varied sensitivities to infection which may influence the phenotype of the resulting models.…”

Section: Reviewmentioning

confidence: 99%

Technical challenges and limitations of current mouse models of ovarian cancer

et al. 2012

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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.

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Mutual Contribution of Pten and Estrogen to Endometrial Carcinogenesis in a PtenloxP/loxP Mouse Model

Cited by 14 publications

References 21 publications

Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities

Ovarian insufficiency and CTNNB1 mutations drive malignant transformation of endometrial hyperplasia with altered PTEN/PI3K activities

Elevated Serum Levels of Estradiol Induce Endometrial Hyperplasia Rather than Carcinoma in a Mouse Model Using a Carcinogen

Technical challenges and limitations of current mouse models of ovarian cancer

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