Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors

Melissa A. Merritt, Howard Strickler, Mark H. Einstein, Hannah P. Yang, Mark E. Sherman, Nicolas Wentzensen, Jurriaan Brouwer-Visser, Maria Jose Cossio, Kathleen D. Whitney, Herbert Yu, Marc J. Gunter, Gloria S. Huang

Research output: Contribution to journalArticle

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Abstract

Purpose: Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology. Methods: We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively. Results: In postmenopausal women, we observed higher levels of phosphorylated IGF-I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values ≤0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values ≤0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values ≤0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values ≤0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01). Conclusions: These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalCancer Causes and Control
DOIs
StateAccepted/In press - Apr 28 2016

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Gonadal Steroid Hormones
Somatomedins
Endometrial Neoplasms
Endometrium
Growth Hormone
Insulin
Insulin Receptor
Carcinogenesis
IGF Type 1 Receptor
Messenger RNA
Live Birth
Progesterone Receptors
Hysterectomy
Insulin-Like Growth Factor I
Estrogen Receptors
Real-Time Polymerase Chain Reaction
Estrogens
Proteins
Anti-Inflammatory Agents
Immunohistochemistry

Keywords

  • Endometrial cancer
  • Endometrium
  • Estrogen receptor
  • Insulin
  • Insulin-like growth factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Merritt, M. A., Strickler, H., Einstein, M. H., Yang, H. P., Sherman, M. E., Wentzensen, N., ... Huang, G. S. (Accepted/In press). Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors. Cancer Causes and Control, 1-12. https://doi.org/10.1007/s10552-016-0751-4

Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors. / Merritt, Melissa A.; Strickler, Howard; Einstein, Mark H.; Yang, Hannah P.; Sherman, Mark E.; Wentzensen, Nicolas; Brouwer-Visser, Jurriaan; Cossio, Maria Jose; Whitney, Kathleen D.; Yu, Herbert; Gunter, Marc J.; Huang, Gloria S.

In: Cancer Causes and Control, 28.04.2016, p. 1-12.

Research output: Contribution to journalArticle

Merritt, MA, Strickler, H, Einstein, MH, Yang, HP, Sherman, ME, Wentzensen, N, Brouwer-Visser, J, Cossio, MJ, Whitney, KD, Yu, H, Gunter, MJ & Huang, GS 2016, 'Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors', Cancer Causes and Control, pp. 1-12. https://doi.org/10.1007/s10552-016-0751-4
Merritt, Melissa A. ; Strickler, Howard ; Einstein, Mark H. ; Yang, Hannah P. ; Sherman, Mark E. ; Wentzensen, Nicolas ; Brouwer-Visser, Jurriaan ; Cossio, Maria Jose ; Whitney, Kathleen D. ; Yu, Herbert ; Gunter, Marc J. ; Huang, Gloria S. / Insulin/IGF and sex hormone axes in human endometrium and associations with endometrial cancer risk factors. In: Cancer Causes and Control. 2016 ; pp. 1-12.
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AU - Sherman, Mark E.

AU - Wentzensen, Nicolas

AU - Brouwer-Visser, Jurriaan

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AB - Purpose: Experimental and observational data link insulin, insulin-like growth factor (IGF), and estrogens to endometrial tumorigenesis. However, there are limited data regarding insulin/IGF and sex hormone axes protein and gene expression in normal endometrial tissues, and very few studies have examined the impact of endometrial cancer risk factors on endometrial tissue biology. Methods: We evaluated endometrial tissues from 77 premenopausal and 30 postmenopausal women who underwent hysterectomy for benign indications and had provided epidemiological data. Endometrial tissue mRNA and protein levels were measured using quantitative real-time PCR and immunohistochemistry, respectively. Results: In postmenopausal women, we observed higher levels of phosphorylated IGF-I/insulin receptor (pIGF1R/pIR) in diabetic versus non-diabetic women (p value =0.02), while women who reported regular nonsteroidal anti-inflammatory drug use versus no use had higher levels of insulin and progesterone receptors (both p values ≤0.03). We also noted differences in pIGF1R/pIR staining with OC use (postmenopausal women only), and the proportion of estrogen receptor-positive tissues varied by the number of live births and PTEN status (premenopausal only) (p values ≤0.04). Compared to premenopausal proliferative phase women, postmenopausal women exhibited lower mRNA levels of IGF1, but higher IGFBP1 and IGFBP3 expression (all p values ≤0.004), and higher protein levels of the receptors for estrogen, insulin, and IGF-I (all p values ≤0.02). Conversely, pIGF1R/pIR levels were higher in premenopausal proliferative phase versus postmenopausal endometrium (p value =0.01). Conclusions: These results highlight links between endometrial cancer risk factors and mechanistic factors that may contribute to early events in the multistage process of endometrial carcinogenesis.

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