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, Zhenlin Ju, Ingvild Løberg Tangen, Anna Berg, Karl Henning Kalland, Anne Margrete Øyan, Line Bjørge, Shannon N. Westin, Camilla Krakstad, Jone Trovik, Gordon Mills, Erling A. Hoivik, Henrica Maria Johanna Werner

Research output: Contribution to journalArticle

2 Citations (Scopus)

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). 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.

Original languageEnglish (US)
Pages (from-to)106989-107001
Number of pages13
JournalOncotarget
Volume8
Issue number63
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Endometrial Neoplasms
Leptin
Proteomics
Hormones
Body Mass Index
Progesterone Receptors
Neoplasms
Obesity
Protein Array Analysis
Proteins
Survival
Gene Expression Profiling
Phosphatidylinositol 3-Kinases
Estrogen Receptors
Estrogens
Immunohistochemistry
Inflammation
Weights and Measures
Genes

Keywords

  • Biomarkers
  • Endometrial cancer
  • Hormone receptors
  • MAPK signaling
  • Obesity

ASJC Scopus subject areas

  • Oncology

Cite this

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; Ju, Zhenlin; Tangen, Ingvild Løberg; Berg, Anna; Kalland, Karl Henning; Øyan, Anne Margrete; Bjørge, Line; Westin, Shannon N.; Krakstad, Camilla; Trovik, Jone; Mills, Gordon; Hoivik, Erling A.; Werner, Henrica Maria Johanna.

In: Oncotarget, Vol. 8, No. 63, 01.01.2017, p. 106989-107001.

Research output: Contribution to journalArticle

Mauland, KK, Ju, Z, Tangen, IL, Berg, A, Kalland, KH, Øyan, AM, Bjørge, L, Westin, SN, Krakstad, C, Trovik, J, Mills, G, Hoivik, EA & Werner, HMJ 2017, 'Proteomic profiling of endometrioid endometrial cancer reveals differential expression of hormone receptors and MAPK signaling proteins in obese versus non-obese patients', Oncotarget, vol. 8, no. 63, pp. 106989-107001. https://doi.org/10.18632/oncotarget.22203
Mauland, Karen Klepsland ; Ju, Zhenlin ; Tangen, Ingvild Løberg ; Berg, Anna ; Kalland, Karl Henning ; Øyan, Anne Margrete ; Bjørge, Line ; Westin, Shannon N. ; Krakstad, Camilla ; Trovik, Jone ; Mills, Gordon ; Hoivik, Erling A. ; Werner, Henrica Maria Johanna. / Proteomic profiling of endometrioid endometrial cancer reveals differential expression of hormone receptors and MAPK signaling proteins in obese versus non-obese patients. In: Oncotarget. 2017 ; Vol. 8, No. 63. pp. 106989-107001.
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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). 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.",
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