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

// Karen Klepsland Mauland 1, 2 , Zhenlin Ju 3 , Ingvild Løberg Tangen 1, 2 , Anna Berg 1, 2 , Karl-Henning Kalland 1, 4 , Anne Margrete Øyan 1, 4 , Line Bjørge 1, 2 , Shannon N. Westin 5 , Camilla Krakstad 1, 6 , Jone Trovik 1, 2 , Gordon B. Mills 7 , Erling A. Hoivik 1, 2 and Henrica Maria Johanna Werner 1, 2 1 Centre for Cancer Biomarkers CCBIO, Department of Clinical Science (K2), University of Bergen, Bergen, Norway 2 Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway 3 Department of Bioinformatics and Computational Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 4 Department of Microbiology, Haukeland University Hospital, Bergen, Norway 5 Department of Gynecologic Oncology and Reproductive Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA 6 Centre for Cancer Biomarkers CCBIO, Department of Biomedicine, University of Bergen, Bergen, Norway 7 Department of Systems Biology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Correspondence to: Karen Klepsland Mauland, email: Karen.Mauland@uib.no Henrica Maria Johanna Werner, email: Henrica.Werner@uib.no Keywords: endometrial cancer; obesity; biomarkers; hormone receptors; MAPK signaling Received: April 27, 2017 Accepted: September 20, 2017 Published: October 31, 2017 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 α S118 (p-ERα) 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-ERα 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-ERα 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.