Abstract PS17-59: Comparative study of breast tumors with differential expression of intracellular energy sensor adenosine monophosphate kinase

Abstract

Abstract Adenosine monophosphate kinase (AMPK), encoded by mammalian gene PRKAA1 is a central energy sensor which acts as a metabolic switch and directs cellular response based on AMP/ATP ratio in cells. AMPK has been shown to be involved in tumorigenesis as part of metabolic reprogramming. Further, chronic metabolic disorders like obesity and insulin dependent diabetes are linked to increased cancer recurrence and poor prognosis. Interestingly, AMPK expression and activity are affected in both obesity and insulin dependent diabetes. Structurally, AMPK is a heterotrimeric protein with alpha (α), beta (β) and gamma (γ) subunits. AMPKα subunit is the catalytic subunit, AMPKβ is the scaffold subunit and AMPKγ subunit provides the competitive binding site for AMP or ATP. In case of nutrient/ energy deprivation, AMP/ATP cellular ratio increases, and AMPK is activated to suppress anabolic pathways and promote catabolic pathways. On the other hand, under excess nutrient, AMP/ATP cellular ratio is decreased, and AMPK function is impeded leading to promotion of anabolic pathways over catabolic pathways. In metabolic disorders like obesity and insulin dependent diabetes, AMPK expression and function are suppressed. Current literature and our research indicate that AMPK can be the bridge between understanding the links between metabolic disorders and cancer. In the current study, we explored the clinical and molecular differences between breast tumors expressing relatively low and high AMPK, indicated as AMPKlow and AMPKhi breast tumors. The cBioPortal (http://cbioportal.org) for Cancer Genomics platform was used for this study. The data mining was focused on METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) Breast cancer study, which reports clinical and molecular data for over 2500 breast cancer patients. Among the 2500 breast cancer tumors, AMPKhi and AMPKlow expressing breast tumors were 310 and 311 in numbers, respectively. The AMPKhi and AMPKlow expressing breast tumors in RNA-seq dataset were queried using cBioPortal embedded SQL feature as PRKAA1: EXP>1 and PRKAA1: EXP<-1, respectively. Comparative analysis of AMPKlow and AMPKhi expressing breast tumors was performed for clinical impact and mRNA expression profiles. The mRNA data was further analyzed for integrated networks using Reactome. The query for AMPKhi and AMPKlow resulted in non-overlapping cohorts of breast tumors. Analysis revealed that significantly higher percentage (65.45%) of AMPKlow breast tumors were positive for Estrogen receptor with high proliferative index. Overall patient survival (months) is significantly more in patients with AMPKhi breast tumors compared to patients with AMPKlow breast tumors. Microarray mRNA expression data revealed unique profile of mRNA expression in both the cohorts. The top 10 most significant differentially expressed genes are KLHL2, COX6C, SLC29A3, SPRY2, RAMP1, ANXA3, HAGH, TLCD3B, KLHL24 and ACVR2A. Pathway enrichment analysis with the top 100 differentially expressed mRNA using Reactome suggested significant enrichment of Wnt, Notch, MAPK and ESR signaling pathways. The molecular profile of AMPKhi and AMPKlow expressing breast tumors are unique and have different mRNA expression signatures. In addition, cancer stem cell homeostasis signaling pathways seem to be critical in the molecular functioning of the two groups. Clinical and molecular data suggests that further investigations into the two molecular subtypes of breast cancer can provide useful insight towards the links between metabolic disorders and cancer. Citation Format: Roxanne L. Lopez, Dorothy Dean, Sushmita Nandy. Comparative study of breast tumors with differential expression of intracellular energy sensor adenosine monophosphate kinase [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 PS17-59.