TY - JOUR
T1 - Proteomic profiling of endometrioid endometrial cancer reveals differential expression of hormone receptors and MAPK signaling proteins in obese versus non-obese patients
AU - Mauland, Karen Klepsland
AU - Ju, Zhenlin
AU - Tangen, Ingvild Løberg
AU - Berg, Anna
AU - Kalland, Karl Henning
AU - Øyan, Anne Margrete
AU - Bjørge, Line
AU - Westin, Shannon N.
AU - Krakstad, Camilla
AU - Trovik, Jone
AU - Mills, Gordon B.
AU - Hoivik, Erling A.
AU - Werner, Henrica Maria Johanna
N1 - Funding Information:
This study was supported by the University of Bergen, the Western Norwegian Regional Health Authority, the Research Council of Norway and the Norwegian Cancer Society.
PY - 2017
Y1 - 2017
N2 - 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). Nonobese patients had higher p-MAPK levels, whereas obese patients had higher p-ERa 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-ERa 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.
AB - 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). Nonobese patients had higher p-MAPK levels, whereas obese patients had higher p-ERa 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-ERa 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.
KW - Biomarkers
KW - Endometrial cancer
KW - Hormone receptors
KW - MAPK signaling
KW - Obesity
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U2 - 10.18632/oncotarget.22203
DO - 10.18632/oncotarget.22203
M3 - Article
C2 - 29291005
AN - SCOPUS:85036668503
SN - 1949-2553
VL - 8
SP - 106989
EP - 107001
JO - Oncotarget
JF - Oncotarget
IS - 63
ER -