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Proteomic profiling of endometrioid endometrial cancer reveals differential expression of hormone receptors and MAPK signaling proteins in obese versus non-obese patients.

ABSTRACT: Endometrial cancer development is strongly linked to obesity, but knowledge regarding the influence of excess weight on endometrial tumor signaling pathways remains scarce. We therefore analyzed reverse phase protein array (RPPA) data for obesity-related protein expression patterns, using one training (n=272) and two test cohorts (n=68; n=178) of well-annotated samples from women treated for endometrioid endometrial cancer. Gene expression profiling and immunohistochemistry were used for cross-platform validation. Body mass index (BMI) was significantly correlated with progesterone receptor (PR) expression and a hormone receptor protein signature, across all cohorts. In two of the cohorts, BMI was negatively correlated with RTK- and MAPK-pathway activation, particularly phosphorylated MAPK T202 Y204 (p-MAPK) level. Using stepwise selection modelling, a BMI-associated protein signature, including phosphorylated estrogen receptor ? S118 (p-ER?) and p-MAPK, was identified. In the subset of FIGO stage 1, grade 1-2 tumors, obese patients (BMI?30) had better survival compared to non-obese patients in the two cohorts with longest follow-up time (p=0.042, p=0.058). Non-obese patients had higher p-MAPK levels, whereas obese patients had higher p-ER? levels and enrichment of gene signatures related to estrogen signaling, inflammation, immune signaling and hypoxia. In subgroup analysis of non-obese patients with FIGO stage 1 tumors, low PI3K-activation was associated with reduced survival (p=0.002, training cohort). In conclusion, increasing BMI is associated with increased PR and p-ER? levels and reduced MAPK signaling, both in all patients and in subsets with predicted excellent prognosis. The MAPK-pathway represents a potential therapeutic target in non-obese patients with low stage and low grade tumors.

SUBMITTER: Mauland KK

PROVIDER: S-EPMC5739790 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Proteomic profiling of endometrioid endometrial cancer reveals differential expression of hormone receptors and MAPK signaling proteins in obese versus non-obese patients.

Mauland Karen Klepsland KK Ju Zhenlin Z Tangen Ingvild Løberg IL Berg Anna A Kalland Karl-Henning KH Øyan Anne Margrete AM Bjørge Line L Westin Shannon N SN Krakstad Camilla C Trovik Jone J Mills Gordon B GB Hoivik Erling A EA Johanna Werner Henrica Maria HM

Oncotarget 20171031 63

Endometrial cancer development is strongly linked to obesity, but knowledge regarding the influence of excess weight on endometrial tumor signaling pathways remains scarce. We therefore analyzed reverse phase protein array (RPPA) data for obesity-related protein expression patterns, using one training (n=272) and two test cohorts (n=68; n=178) of well-annotated samples from women treated for endometrioid endometrial cancer. Gene expression profiling and immunohistochemistry were used for cross-p ...[more]

PMID: 29291005

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Project description:The objective of this study was to determine whether lower expression levels of DICER1 are associated with disease recurrence in patients with endometrioid endometrial cancer. The authors also explored DNA methylation and haploinsufficiency as potential mechanisms related to altered DICER1 expression in these tumors.DICER1 expression was assessed by quantitative polymerase chain reaction in a selected cohort of endometrioid endometrial tumors (N = 169). Loss of heterozygosity analyses were conducted using 2 single nucleotide polymorphisms, and combined bisulfate restriction analysis was used to assess methylation in the 5'-untranslated region of DICER1 in representative tumors. The correlations between DICER1 expression and clinicopathologic variables, including overall survival (OS) and disease-free survival (DFS), were assessed using nonparametric rank-sum tests and Cox proportional hazard models as appropriate. Survival distributions were described using the Kaplan-Meier method. A nested case-control analysis was conducted to confirm the association between transcript levels and disease recurrence.Lower DICER1 expression (hazard ratio [HR], 1.36; 95% confidence interval [CI], 1.05-1.75; P = .02) and advanced disease stage (HR, 2.79; 95%CI, 1.59-4.90; P < .001) were associated with worse DFS. Three variables were associated significantly with reduced OS: age (HR, 1.04; 95%CI, 1.02-1.06; P < .0001), advanced disease stage (HR, 6.41; 95%CI, 3.57-11.52; P < .0001), and high tumor grade (HR, 2.96; 95%CI, 1.46-5.99; P = .003). Nested case-control analyses confirmed that there were lower DICER1 transcript levels in patients who had recurrent disease (P = .01). Deletion of DICER1 sequences was an infrequent event (5% of analyzed patients), and no methylation was observed in the 5' DICER1 regulatory region.Lower DICER1 transcript levels were correlated with disease recurrence and worse DFS survival in patients with endometrioid endometrial cancer. The factors that influence DICER1 transcript levels in primary endometrial cancers remain unknown.

Project description:Uterine cancers are among the most prevalent gynecological malignancies, and endometrial cancer (EC) is the most common in this group. This study used tissue-based proteomic profiling analysis in patients with endometrial cancer and hyperplasia, and control patients. Conventional 2D gel electrophoresis, followed by a mass spectrometry approach with bioinformatics, including a network pathway analysis pipeline, was used to identify differentially expressed proteins and associated metabolic pathways between the study groups. Thirty-six patients (twelve with endometrial cancer, twelve with hyperplasia, and twelve controls) were enrolled in this study. The mean age of the participants was 46-75 years. Eighty-seven proteins were significantly differentially expressed between the study groups, of which fifty-three were significantly differentially regulated (twenty-eight upregulated and twenty-five downregulated) in the tissue samples of EC patients compared to the control (Ctrl). Furthermore, 26 proteins were significantly dysregulated (8 upregulated and 18 downregulated) in tissue samples of hyperplasia (HY) patients compared to Ctrl. Thirty-two proteins (nineteen upregulated and thirteen downregulated) including desmin, peptidyl prolyl cis-trans isomerase A, and zinc finger protein 844 were downregulated in the EC group compared to the HY group. Additionally, fructose bisphosphate aldolase A, alpha enolase, and keratin type 1 cytoskeletal 10 were upregulated in the EC group compared to those in the HY group. The proteins identified in this study were known to regulate cellular processes (36%), followed by biological regulation (16%). Ingenuity pathway analysis found that proteins that are differentially expressed between EC and HY are linked to AKT, ACTA2, and other signaling pathways. The panels of protein markers identified in this study could be used as potential biomarkers for distinguishing between EC and HY and early diagnosis and progression of EC from hyperplasia and normal patients.

Dataset Information

Proteomic profiling of endometrioid endometrial cancer reveals differential expression of hormone receptors and MAPK signaling proteins in obese versus non-obese patients.

Publications

Proteomic profiling of endometrioid endometrial cancer reveals differential expression of hormone receptors and MAPK signaling proteins in obese versus non-obese patients.

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