Abstract 151: Obesity is independently associated with mTORC1 pathway activation in the progression of endometrial cancer.
Authors: Libby Emily Falk , Azrad Maria , Novak Lea , Demark-Wahnefried Wendy 
Published: August 2014

Background: Obesity is a major risk factor for endometrial cancer (EC) yet, with the exception of estrogen, the mechanisms underlying this association remain unclear. The mammalian target of rapamycin complex 1 (mTORC1) cascade links energy balance to cell proliferation via the PI3K/Akt pathway. Phosphorylation of Akt by hormone and growth factor signaling activates mTORC1 and results in the downstream phosphorylation of 4EBP1. Activated 4EBP1 positively regulates cap-dependent translation and cell growth, and correlates with EC progression. Thus, we explored the associations between obesity and pAkt and p4EBP1 expression, and cell proliferation rates (Ki67) in benign and malignant endometrial tissues.

Methods: Medical records were reviewed to identify women who underwent endometrial biopsy at UAB Hospital from 2008-2010. Women who had recurrent EC or diagnoses of any other cancer were excluded. Data on diagnosis, height, weight, race, age, menopausal status, number of children, medications, and comorbid conditions were extracted from medical records. Height and weight were used to calculate body mass index (BMI: kg/m2). A gynecologic pathologist reviewed H&E slides for concordance with the pathology report, and additional sections were obtained from formalin-fixed paraffin-embedded tissue blocks. Immunohistochemistry was used to assess p4EBP1, pAkt, and Ki67. The pathologist employed a semiquantitative scoring system based on percent positive and staining intensity for p4EBP1 and pAkt, and scored on percent positive for Ki67. Wilcoxon rank-sum tests were used to compare marker activity between women with and without EC in the overall and BMI-stratified sample.

Results: Immunohistochemical data were available for 18 benign and 25 type 1 endometrioid EC cases, of which 29 were obese (BMI &gt; 29.9) and 14 were non-obese (BMI ≤ 29.9); the overall mean BMI was 35.5 (SD=11.6). Mean age was 56.7 (12.2). Women with vs. without EC had significantly elevated median [interquartile range] expression of cytoplasmic p4EBP1 (95 [30-180] vs. 0 [0-20], p=0.001), nuclear p4EBP1 (170 [95-195] vs. 70 [20-100], p=0.003), and Ki67 (50 [40-80] vs. 10 [5-20], p&lt;0.0001). EC was not associated with pAKT activity. While obese women with vs. without EC had significantly higher expression of cytoplasmic p4EBP1 (100 [80-180] vs. 0 [0-10], p=0.002) and nuclear p4EBP1 (180 [100-200] vs. 65 [20-100], p=0.002), neither cytoplasmic nor nuclear p4EBP1 activity differed by EC status among non-obese women. No associations between obesity and Ki67 or pAKT were detected.

Conclusions: Results from this exploratory study suggest that p4EBP1 expression is elevated in obese women with EC. These preliminary findings suggest that obesity may play a role in EC-related activation of the mTORC1 pathway and 4EBP1, a biomarker for EC outcomes.

Citation Format: Emily Falk Libby, Maria Azrad, Lea Novak, Wendy Demark-Wahnefried. Obesity is independently associated with mTORC1 pathway activation in the progression of endometrial cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 151. doi:10.1158/1538-7445.AM2013-151