Obesity is associated with higher 4E-BP1 expression in endometrial cancer

Current Biomarker Findings Dovepress open access to scientific and medical research Original Research Open Access Full Text Article Current Biomarker Findings downloaded from https://www.dovepress.com/ by 37.59.46.207 on 13-Jul-2018 For personal use only. Obesity is associated with higher 4E-BP1 expression in endometrial cancer This article was published in the following Dove Press journal: Current Biomarker Findings 15 January 2014 Number of times this article has been viewed Emily Falk Libby 1,* Maria Azrad 1,* Lea Novak 2 Ana I Vazquez 3 Tamara R Wilson 1 Wendy DemarkWahnefried 1 Department of Nutrition Sciences, Department of Pathology, 3 Department of Biostatistics, University of Alabama at Birmingham, Birmingham,  AL, USA 1 2 *These authors contributed equally to this work Purpose: Obesity is associated with risk and prognosis of endometrial cancer (EC), and the mammalian target of rapamycin complex 1 (mTORC1) pathway may play an instrumental role. We sought to explore the associations between cellular proliferation, Akt, and 4E binding protein-1 (4E-BP1) (a downstream target of mTORC1), in obese and nonobese women with and without EC. Methods: Archival tissue-specimens from endometrial biopsies were grouped into two broad categories based on the observed disease behavior and similarities in tissue staining patterns: benign/ hyperplasia (without cytologic atypia) (n=18) versus atypia (complex hyperplasia with cytologic atypia)/carcinoma (n=25). The characteristics of the study population, including height and weight to determine body mass index (BMI: kg/m2), were abstracted from medical records. Immunohistochemistry was used to assess the phosphorylated (p)Akt, p4E-BP1, and antigen Ki67. Results: Cytoplasmic and nuclear pAkt were significantly associated with cytoplasmic p4E-BP1 (ρ=+0.48, ρ=+0.50) (P,0.05) and nuclear p4E-BP1 (ρ=+0.40, ρ=+0.44) (P,0.05); cytoplasmic and nuclear p4E-BP1 were significantly associated with Ki67 (ρ=+0.46, ρ=+0.59) (P,0.05). Compared with the benign/hyperplasia group, the women with atypia/carcinoma had significantly higher cytoplasmic and nuclear p4E-BP1 and Ki67. This staining pattern was similar in obese women; however, in nonobese women, neither cytoplasmic nor nuclear p4E-BP1staining differed between benign/hyperplasia versus atypia/carcinoma. Conclusion: The activation of 4E-BP1 was higher in the obese women with EC. Adiposity may be a key factor to consider in future studies investigating the role of 4E-BP1 as a biomarker and therapeutic target in EC. Keywords: mTORC1, immunohistochemistry, gynecologic malignancy, corpus uterine, BMI, biomarker Introduction Correspondence: Emily Falk Libby University of Alabama at Birmingham, Volker Hall G017, 1670 University Boulevard, Birmingham, AL, 35294-0019, USA Tel +1 205 934 4670 Fax +1 205 975 1126 Email 1 submit your manuscript | www.dovepress.com Current Biomarker Findings 2014:4 1–7 Dovepress © 2014 Libby et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/CBF.S53530 Powered by TCPDF (www.tcpdf.org) Endometrial cancer (EC) is the most common gynecologic cancer in the United States. This year, approximately 47,000 American women will be diagnosed with this malignancy.1 EC was among the first malignancies to be linked with obesity, and there is consensus that excess adiposity is a major risk factor for the disease.2 Overweight and obese women are two to three times more likely to develop EC compared with women of normal weight.3 Given that 64% of American women are overweight or obese and therefore, at risk for EC, there is a critical need to better understand the molecular mechanisms and associated biomarkers linking excess adiposity with this prevalent disease.4 Obesity alters the hormonal milieu in ways that can promote the development of EC. The higher concentrations of estrogen seen in overweight and obese postmenopausal Dovepress Current Biomarker Findings downloaded from https://www.dovepress.com/ by 37.59.46.207 on 13-Jul-2018 For personal use only. Libby et al women are recognized as a major risk factor for developing precancerous and cancerous lesions of the uterus.3 The results of several recent laboratory and epidemiological studies suggest that other endocrine-related mechanisms associated with adiposity may also be linked with EC.5 Insulin and leptin stimulate the proliferation of EC cells in vitro6,7 and positively correlate with endometrial cell proliferation rates in the normal tissue of women who are normal weight, overweight, and obese.8 In contrast, adiponectin, which is typically reduced with excess adiposity,9 may be protective against EC, by inducing cell cycle arrest and apoptosis.10 The hormonal disturbances associated with obesity can mediate cell proliferation via intracellular signaling pathways. At the molecular level, insulin and leptin both phosphorylate and activate Akt, which in turn activates the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a key pathway that links growth factors, hormones, and energy balance with cell proliferation. 11 Conversely, adiponectin has been shown to inhibit mTORC1, partly through dephosphorylation of Akt via the activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK).12 One of the downstream targets of mTORC1 is the eukaryotic initiation factor 4E (elF4E)/eukaryotic initiation factor 4E binding protein-1 (4E-BP1) complex. When phosphorylated by mTORC1, 4E-BP1 releases eIF4E, a key mediator of messenger ribonucleic acid (mRNA) translation and protein synthesis, resulting in increased cell growth and proliferation.13 Thus, the upstream phosphorylation of Akt by growth factors and the downstream phosphorylation of 4E-BP1 are biomarkers, not only of mTORC1 activity, but also of cell growth and proliferation.11 Previous studies have shown that activation of the Akt/mTOR pathway is involved in EC and that this pathway is a potential therapeutic target for the disease.14−16 Further, the activation of 4E-BP1 has been linked to poorer EC prognosis, rendering it a plausible candidate for biomarker development.17−19 However, the role that obesity, a modifiable risk factor for EC, plays in mTORC1 signaling is unclear. Thus, we performed an exploratory study to examine the associations between phosphorylated (p)Akt, phosphorylated 4E-BP1 (p4E-BP1), and cellular proliferation rates (indicated by the cell marker antigen Ki67), in (...truncated)