Rapid Estrogen Signaling Negatively Regulates PTEN Activity Through Phosphorylation in Endometrial Cancer Cells

Scully, Melanie; Palacios-Helgeson, Leslie K.; Wah, Lah S.; Jackson, Twila A.

doi:10.1007/s12672-014-0184-z

Cited by 15 publications

(11 citation statements)

References 59 publications

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“…Further, the lower expression of PTEN in tumor epithelial cells (~4× lower than in tumor stroma; Fig. 2d) concurs with PTEN loss in tumor epithelial cells as a diagnostic marker of endometrial pre-cancers [36] and with the linkage between loss of PTEN and activation of ERα signaling in EC [37,38]. While it is not possible to directly compare the MET-elicited changes in epithelial ERα, PGR, and KLF9 proteins in vivo with those of the time-dependent changes in their respective transcripts in Ishikawa cells in vitro, it is noteworthy that the in vitro responses to MET were achieved at a concentration (60 μM) significantly less than previously reported (predominantly mM and hence pharmacological range) for most studies.…”

Section: Discussionsupporting

confidence: 66%

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

et al. 2020

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Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67-and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 μM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.

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Section: Discussionsupporting

confidence: 66%

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

et al. 2020

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“…In endometrial carcinoma, particularly in type I, mutations of PTEN have been described to occur in 25–83% of cases; however, mutations of PTEN have also been described to occur in endometrial hyperplasia (~55%) (13,15,84–88). In a study by Lacey et al (26), loss of PTEN expression in biopsies of endometrial hyperplasia was not associated with subsequent risk of endometrial carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Expression of p53 and PTEN in human primary endometrial carcinomas: Clinicopathological and immunohistochemical analysis and study of their concomitant expression

et al. 2019

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Endometrial carcinoma is a common malignancy of the female genital tract. Alterations in the expression levels of various oncogenes and tumor suppressor genes serve important roles in the carcinogenesis and biological behavior of endometrial carcinoma. The aim of the present study was to evaluate the combination and individual expression of p53 and phosphatase and tensin homolog (PTEN) protein in human endometrial carcinoma. In addition, the correlation of these proteins with clinicopathological parameters was also assessed. Retrospective immunohistochemical analysis of the expression of p53 and PTEN tumor suppressor proteins was conducted in 99 women with endometrial carcinoma. The overall rate of p53 and PTEN positivity was 89 and 77%, respectively, according to the sum of stain intensity and scores of immunopositive cells. The sum of p53 positivity correlated strongly with PTEN expression (ρ=0.256; P=0.044). The concomitant sum of p53 and PTEN expression was identified in 45% of patients with endometrial adenocarcinoma. Notably, the sum of the immunohistochemical expression of p53 was significantly correlated with patient age (P=0.037), histologic type (P=0.008), histologic grade (P=0.002) and fallopian and/or ovarian invasion (P=0.014). Furthermore, PTEN expression was associated with myometrial invasion (ρ=−0.377; P=0.002) and clinical stage (P=0.019). In addition, concomitant p53 and PTEN expression was correlated with patient age (P=0.008) and histologic differentiation (P=0.028). The findings indicated a correlation between the expression of p53 and PTEN in endometrial adenocarcinoma, which suggested an intrinsic association between expression levels of these tumor suppressor genes. The study also suggested that concomitant p53 and PTEN expression contributed in characterizing the tumor behavior of endometrial carcinoma. Taken together, the present study suggested the combined expression of p53 and PTEN in the development of high-grade endometrial carcinoma in older patients. In addition, the findings indicated activation of different molecular pathways in the tumor progression between low-grade and high-grade endometrial carcinomas.

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“…Activation of PI3K has been shown to induce activation of primordial follicles in mice (Reddy et al 2008 ). Also, estradiol increases phosphorylation and decreases activity of PTEN in vitro (Scully et al 2014 ).…”

Section: Adverse Outcome Pathways As They Relate To Key Processes In mentioning

confidence: 99%

Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

et al. 2020

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Modern living challenges female reproductive health. We are witnessing a rise in reproductive disorders and drop in birth rates across the world. The reasons for these manifestations are multifaceted and most likely include continuous exposure to an ever-increasing number of chemicals. The cause–effect relationships between chemical exposure and female reproductive disorders, however, have proven problematic to determine. This has made it difficult to assess the risks chemical exposures pose to a woman’s reproductive development and function. To address this challenge, this review uses the adverse outcome pathway (AOP) concept to summarize current knowledge about how chemical exposure can affect female reproductive health. We have a special focus on effects on the ovaries, since they are essential for lifelong reproductive health in women, being the source of both oocytes and several reproductive hormones, including sex steroids. The AOP framework is widely accepted as a new tool for toxicological safety assessment that enables better use of mechanistic knowledge for regulatory purposes. AOPs equip assessors and regulators with a pragmatic network of linear cause–effect relationships, enabling the use of a wider range of test method data in chemical risk assessment and regulation. Based on current knowledge, we propose ten putative AOPs relevant for female reproductive disorders that can be further elaborated and potentially be included in the AOPwiki. This effort is an important step towards better safeguarding the reproductive health of all girls and women.

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Rapid Estrogen Signaling Negatively Regulates PTEN Activity Through Phosphorylation in Endometrial Cancer Cells

Cited by 15 publications

References 59 publications

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

Expression of p53 and PTEN in human primary endometrial carcinomas: Clinicopathological and immunohistochemical analysis and study of their concomitant expression

Putative adverse outcome pathways for female reproductive disorders to improve testing and regulation of chemicals

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