Adiponectin, Leptin, and Insulin-Pathway Receptors as Endometrial Cancer Subtyping Markers

Abstract

Developing a system of molecular subtyping for endometrial tumors might improve insight into disease etiology and clinical prediction of patient outcomes. High body mass index (BMI) has been implicated in development of endometrial cancer through hormonal pathways and might influence tumor expression of biomarkers involved in BMI-sensitive pathways. We evaluated whether endometrial tumor expression of 7 markers from BMI-sensitive pathways of insulin resistance could effectively characterize molecular subtypes: adiponectin receptor 1, adiponectin receptor 2, leptin receptor, insulin receptor (beta subunit), insulin receptor substrate 1, insulin-like growth factor 1 receptor, and insulin-like growth factor 2 receptor. Using endometrial carcinoma tissue specimens from a case-only prospective sample of 360 women from the Nurses' Health Study, we scored categorical immunohistochemical measurements of protein expression for each marker. Logistic regression was used to estimate associations between endometrial cancer risk factors, especially BMI, and tumor marker expression. Proportional hazard modeling was performed to estimate associations between marker expression and time to all-cause mortality as well as time to endometrial cancer-specific mortality. No association was observed between BMI and tumor expression of any marker. No marker was associated with time to either all-cause mortality or endometrial cancer-specific mortality in models with or without standard clinical predictors of patient mortality (tumor stage, grade, and histologic type). It did not appear that any of the markers evaluated here could be used effectively to define molecular subtypes of endometrial cancer.

Clinical value of selected markers of angiogenesis, inflammation, insulin resistance and obesity in type 1 endometrial cancer

“…Circulating adipokines, like adiponectin, have a systemic immunomodulatory effect, also play an important role in the development of selected types of cancer. Prospective studies have shown that insulin, IGFBP2, leptin, adiponectin, and C-peptide play an important role in the development of EC [12]. Most cancer-related epidemiological studies have revealed that the risk for type 1 EC development is strongly correlated with obesity.…”

Estradiol metabolites as biomarkers of endometrial cancer prognosis after surgery

“…EC prevails after menopause when ovaries have ceased to secrete potent estrogens. Obesity is a known risk factor of EC [4] and this may be partly related to the fact that adipose tissue represents a major source of estrogen synthesis in postmenopausal women, actively converting adrenal and androgen precursors to estrogens resulting in increased serum bioavailable estradiol (E 2 ) [5,6]. Previous work by our group and others has revealed that the potent estrogen E 2 primarily derive from conversion of estrone-sulfate (E 1 -S) in EC tumors rather than aromatization of androgens by the aromatase (CYP19), which has barely detectable expression levels in EC cells [7][8][9][10].…”

“…In addition, these metabolites can be converted to their inactive sulfate and glucuronide conjugates. Recent studies have assessed the risk of EC in relation to steroid hormones, yet none have explored their association with prognosis [4,14].…”

Insulin Resistance and Endometrial Cancer: Emerging Role for microRNA

“…On the other hand, Ma et al observed increased leptin and decreased adiponectin levels in EC [126]. Unfortunately, adiponectin and leptin concentrations and insulin pathway receptor expressions were not found useful for defining molecular subtypes of EC [127]. Moreover, molecular links between adipokines and cancer cells are complex and as yet, are not fully understood [128].…”