Abstract
Abstract Metabolic dysregulation and carcinogenesis are strongly linked. Leptin signaling acts as a metabolic switch that maintains body weight and energy homeostasis and gets impacted during metabolic dysregulation. Leptin signaling mediates its effect on breast cancer cells through downstream effectors like JAK-STAT, MAPK and PI3K pathways. At the molecular level, leptin exerts its effects through its receptor, LEPR, encoded by LEPR gene. Leptin signaling has been shown to contribute towards progression of breast cancer. Obese post-menopausal women are considered to be a high-risk category for breast cancer and dysregulated leptin signaling contributes towards it. We in this study focused on comparative molecular analysis of Leptin high (LEPRhi) and low (LEPRlow) expressing breast tumors.Breast cancer data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) study was used through the cBioPortal (http://cbioportal.org) platform for cancer genomics. The METABRIC study includes clinical and molecular data from over 2500 breast cancer cases. The LEPRhi and LEPRlow expressing breast tumors in RNA-seq dataset were queried using cBioPortal embedded SQL feature as LEPR: EXP>1 and LEPR: EXP<-1 respectively. This query enabled us to create LEPRhi and LEPRlow expressing breast tumor cohorts from 243 and 234 patients respectively. Comparative analysis of LEPRhi and LEPRlow expressing breast tumors was performed for mRNA expression profiles. The mRNA data was further analyzed for integrated networks using GSEA pathway enrichment and CR2-cancer algorithms.The analysis indicated unique mRNA expression signature for LEPRhi and LEPRlow breast tumors. CR2-Cancer analysis of the mRNA dataset revealed chromatin modulators like- EZH2 (Enhancer of Zeste homolog 2), MEN1 (Menin), UHRF1 (Ubiquitin Like with PHD And Ring Finger Domains 1), TTF2 (Transcription termination factor 2), LMNB2 (Lamin B2), and RUVBL2 (RuvB Like AAA ATPase 2) had significantly higher mRNA expression in LEPRlow compared to LEPRhi tumor group. GSEA pathway enrichment analysis indicated PLK1 and Aurora A signaling as the most significant signaling pathways with an FDR q-value of less than 0.05.This preliminary study provides us with mechanistic insight into the unique molecular signatures of LEPRhi and LEPRlow expressing breast tumors. The results of this study leads to the basis of our hypothesis that leptin receptor signaling in breast cancer mediates epigenetic modifications of key genes that impact promotion and progression of breast cancer through chromatin modulators. Citation Format: Sara Pacheco, Maria E. Juarez, Sushmita Nandy. Leptin receptor expression in breast tumors and chromatin modulators: A comparative study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-51.
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