Abstract 435: Is PYGM dysregulation involved in breast cancer cell metabolism

Abstract

Abstract Many anticancer targets with role in drug resistance are involved in key metabolic processes. In recent years, the interest in targeting cell metabolism and metabolic pathways connected to energy storage and redox potential has been renewed. Comparative analyses of paired samples of tumor cells and corresponding normal tissue can reveal the altered metabolite profiles and can increase the understanding of metabolic involvement in cancer progression. By applying whole exome sequencing on eight pairs of pleiomorphic lobular carcinoma frozen samples, an aggressive breast cancer subtype, and matched normal tissue, we recently identified recurrent somatic mutations in four genes. Three of these genes are already described to be implicated in breast cancer (PIK3CA, TP53 and CDH1), and one novel mutated gene was identified: PYGM which encodes for glycogen phosphorylase firstly isolated from muscular tissue. Targeted sequencing performed on 27 pleiomorphic lobular carcinoma samples confirmed PYGM as a frequently mutated gene in this pathology (30%). Subsequent analysis of the breast gene expression TCGA dataset uncovered that PYGM is significantly downregulated in breast cancer samples compared to normal breast tissue, irrespectively of the breast cancer molecular subtype. The same trend was observed in other cancer types, such as colon, bladder or head and neck carcinoma, after analysis of publicly available gene expression databases. PYGM is expressed in many other cell types and initiates the breakdown of glycogen by degradation in glucose-1-phosphate, which can be enzymatically converted to glucose-6-phosphate. This generates an alternative cellular energy source to immediate ATP. In muscle cells, various mutations impairing PYGM activity lead to McArdle disease (autosomic recessive glycogen storage disease type V) which is characterized by exercise intolerance, pain, muscle weakness, and cramps. In cancer cells, some few abnormalities of PYGM have been reported. We thus investigated the potential dysregulation of PYGM expression and/or function in breast cancer and its consequences on cell metabolism. We found that PYGM expression is downregulated in breast cancer tissue compared to paired normal tissue. In order to analyze the role of PYGM in preclinical models, we established new breast cancer cell lines overexpressing PYGM. Biochemical and molecular analyses are ongoing to investigate cell behavior according to PYGM expression level in various culture conditions and will inform us about a potential efficacy of PYGM targeting in new therapy development based on metabolic biomarkers applied to breast cancer treatment. Citation Format: Veronika SMUTNA, Maria Vittoria DIECI, Céline LEFEBVRE, Véronique SCOTT, Fabrice ANDRE, Olivia FROMIGUE. Is PYGM dysregulation involved in breast cancer cell metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 435. doi:10.1158/1538-7445.AM2014-435