Conditional Loss of Uterine <i>Pten</i> Unfailingly and Rapidly Induces Endometrial Cancer in Mice

Daikoku, Takiko; Hirota, Yasushi; Tranguch, Susanne; Joshi, Ayesha R.; DeMayo, Francesco J.; Lydon, John P.; Ellenson, Lora Hedrick; Dey, Sudhansu K.

doi:10.1158/0008-5472.can-08-1274

Cited by 205 publications

(231 citation statements)

References 42 publications

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“…Regenerated tumors resulting from loss of PTEN in this in vivo model exhibit normal expression of PTEN in the stroma with loss of PTEN in the epithelium. Currently published PTEN mouse models result in concomitant loss of PTEN in the epithelium and stroma (4,5). Although the consequences of stromal PTEN loss in the endometrium are unknown, loss of PTEN in mammary stromal cells has been shown to promote tumor formation in cooperation with cell-autonomous genetic changes (30).…”

Section: Discussionmentioning

confidence: 99%

“…In this model, one allele of PTEN is deleted in all tissues (4). In an alternative model, mice with progesterone receptor (PR) promoter-driven Cre were crossed with a PTEN loxP/loxP strain, resulting in endometrial hyperplasia in prepubertal mice progressing to type I endometrial carcinoma in adult animals (5). Because PR is expressed in uterine epithelium and stroma, it is unclear whether the observed tumors in this model result from genetic alterations in the uterine epithelium, stroma, or both.…”

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confidence: 99%

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Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Memarzadeh¹,

Zong

Janzen³

et al. 2010

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

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Epithelial-specific activation of the PI3-kinase pathway is the most common genetic alteration in type I endometrial cancer. In the majority of these tumors, PTEN expression is lost in the epithelium but maintained in tumor stroma. Currently reported PTEN knockout mouse models initiate type I endometrial cancer concomitant with loss of PTEN in both uterine epithelium and stroma. Consequently, the biologic outcome of selectively activating the PI3-kinase pathway in the endometrial epithelium remains unknown. To address this question, we established a malleable in vivo endometrial regeneration system from dissociated murine uterine epithelium and stroma. Regenerated endometrial glands responded to pharmacologic variations in hormonal milieu similar to the native endometrium. Cellautonomous activation of the PI3-kinase pathway via biallelic loss of PTEN or activation of AKT in adult uterine epithelia in this model was sufficient to initiate endometrial carcinoma. AKT-initiated tumors were serially transplantable, demonstrating permanent genetic changes in uterine epithelia. Immunohistochemistry confirmed loss of PTEN or activation of AKT in regenerated hyperplastic glands that were surrounded by wild-type stroma. We demonstrate that cell-autonomous activation of the PI3-kinase pathway is sufficient for the initiation of endometrial carcinoma in naive adult uterine epithelia. This in vivo model provides an ideal platform for testing the response of endometrial carcinoma to targeted therapy against this common genetic alteration.tissue regeneration model | progesterone receptor | uterine cancer E ndometrial cancer, the most common gynecologic cancer in the United States (1), is a hormonally regulated tumor arising from epithelial cells lining the uterine cavity. Effective targeted therapy is unavailable, partly because of lack of knowledge regarding basic biologic pathways and cellular compartments that can initiate this malignancy. Women diagnosed with endometrial cancer are treated in a similar manner irrespective of the heterogeneity of this disease, with surgery or combinations of radiation and chemotherapy. Although endometrial cancer can be cured in early stages, side effects associated with the current therapy can have lifelong debilitating effects on some patients. The majority of women diagnosed with late-stage or metastatic disease die, despite undergoing radical treatments.Endometrial cancer can be divided into two distinct subtypes (2). Type I tumors occur in younger patients exposed to high levels of estrogen unopposed by progesterone. They are typically localized with better response to hormonal therapy. Type II tumors occur in older patients independent of hormonal status. These tumors are more invasive, have a greater propensity for metastatic spread, and are refractory to hormonal treatment. Activation of distinct biologic pathways has been reported in type I vs. type II cancers. Type I tumors are associated with activation of the PI3-kinase pathway, activating mutations of KRAS, mutant β-catenin, an...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Memarzadeh¹,

Zong

Janzen³

et al. 2010

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

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“…They used the global profiling method [21][22][23][24][25][26][27][28][29] or the candidate miRNA approach [30][31][32][33][34][35][36] and showed that aberrant expression of miRNAs has been associated with tumor histology, [26][27][28] response to steroid therapy 24 or chemotherapy 29 and survival. 21,22,25 However, most studies determined miRNA expression in either normal endometrial tissues or cancer tissues, and the possible miRNA expression in endometrial hyperplasia is largely unknown.…”

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confidence: 99%

Expression of miRNAs and PTEN in endometrial specimens ranging from histologically normal to hyperplasia and endometrial adenocarcinoma

et al. 2012

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We investigated the relationship between frequently deregulated microRNAs (miRNAs) and enodometrial pathology in an attempt to find the most dependable miRNA or combination of miRNAs to identify normal, hyperplastic and malignant endometrial tissues. We also investigated the association between those miRNAs and PTEN status. We measured the expression of six miRNAs (miR-21, 182, 183, 200a, 200c and 205) in 75 formalin-fixed, paraffin-embedded normal, hyperplastic, and malignant endometrial tissue blocks using Taqman-based real-time PCR assays. PTEN loss of expression was assessed in the same endometrial tissues by immunohistochemistry. Expression of five miRNAs (miR-182, 183, 200a, 200c and 205) was significantly higher in endometrial carcinoma (CA) when compared with complex atypical hyperplasia (CAH), simple hyperplasia (SH) and normal endometrial tissue (Po0.05, respectively). Considering the likelihood ratio and number of parameters, the composite panel of six miRNAs was the best marker, revealing a sensitivity of 91% and a specificity of 94% in differentiating endometrial CA from endometrial hyperplasia or normal endometrium while the individual miRNAs exhibited 64-77% sensitivity and 66-91% specificity. Interestingly, in distinguishing endometrial CA from CAH, the composite panel of four miRNAs (miR-182, 183, 200a, 200c) was the best marker, producing 95% sensitivity and 91% specificity. The percentage of PTEN loss was significantly higher in endometrial CA compared with SH (68% vs 24%, Po0.05), and it was also higher in CAH compared with SH (71% vs 24%, Po005). Aberrant expression of miRNAs and loss of PTEN expression are common in endometrial hyperplasia and CA. They might serve to increase the diagnostic reproducibility and improve discrimination, especially, between CAH and CA by miRNA expression profiles and between simple and complex hyperplasia through PTEN expression patterns. Those expression profiles of biomarkers also might be used to predict the potential for progression from endometrial hyperplasia to invasive CA.

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“…As modification of COX signaling is reported in PTEN knockout-induced uterine cancers in which Cox-2 expression was increased in early stages of endometrial cancers in mouse (Daikoku et al 2008), we quantified the Cox-1 and Cox-2 mRNA expression to determine if the expression was modified by PTEN and/or AR knockout. Cox-2 mRNA expression significantly increased by both AR inactivation (P = 0.006; two-way ANOVA) and PTEN deletion (P = 0.013).…”

Section: Cox-2 Gene Expression Was Significantly Increased In Ugeptenmentioning

confidence: 99%

“…Furthermore, conditional homozygous PTEN deletion in the uterus or in uterine epithelial cells resulted in EMC (Daikoku et al 2008, Memarzadeh et al 2010, Mirantes et al 2013, Tirodkar et al 2014, Choi et al 2015b). In our current study, simultaneous glandular epithelial AR inactivation along with PTEN deletion significantly accelerated the severity of uterine pathology from hyperplastic glands (detected in both ugePTENKO and ugePTENARKO uteri) to intraepithelial neoplastic glands with atypia (only in ugePTENARKO uterus).…”

Section: :5mentioning

confidence: 99%

Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology

Choi

Zheng

Handelsman

et al. 2016

Endocrine-Related Cancer

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Phosphatase and tensin homolog (PTEN) deletion induces uterine pathology, whereas androgen actions via androgen receptor (AR) support uterine growth and therefore may modify uterine cancer risk. We hypothesized that the androgen actions mediated via uterine glandular epithelial AR could modify PTEN deletion-induced uterine pathology. To test our hypothesis, we developed uterine glandular epithelium-specific PTEN and/or AR knockout mouse models comparing the uterine pathology among wild-type (WT), glandular epithelium-specific AR inactivation (ugeARKO), PTEN deletion (ugePTENKO), and the combined PTEN and AR knockout (ugePTENARKO) female mice. The double knockout restricted to glandular epithelium showed that AR inactivation enhanced PTEN deletion-induced uterine pathology with development of intraepithelial neoplasia by 20 weeks of age. In ugePTENARKO, 6/10 (60%) developed intraepithelial neoplasia, whereas 3/10 (30%) developed only glandular hyperplasia in ugePTENKO uterus. No uterine pathology was observed in WT (n = 8) and ugeARKO (n = 7) uteri. Uterine weight was significantly (P = 0.002) increased in ugePTENARKO (374 ± 97 mg (mean ± s.e.)) compared with WT (97 ± 6 mg), ugeARKO (94 ± 12 mg), and ugePTENKO (205 ± 33 mg). Estrogen receptor alpha (ERα) and P-AKT expression was modified by uterine pathology but did not differ between ugePTENKO and ugePTENARKO, suggesting that its expressions are not directly affected by androgens. However, progesterone receptor (PR) expression was reduced in ugePTENARKO compared to ugePTENKO uterus, suggesting that PR expression could be regulated by glandular epithelial AR inactivation. In conclusion, glandular epithelial AR inactivation (with persistent stromal AR action) enhanced PTEN deletion-induced uterine pathology possibly by downregulating PR expression in the uterus.Correspondence should be addressed to D J Handelsman

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Conditional Loss of Uterine Pten Unfailingly and Rapidly Induces Endometrial Cancer in Mice

Cited by 205 publications

References 42 publications

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Cell-autonomous activation of the PI3-kinase pathway initiates endometrial cancer from adult uterine epithelium

Expression of miRNAs and PTEN in endometrial specimens ranging from histologically normal to hyperplasia and endometrial adenocarcinoma

Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology

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