LEP and FOXO1 Genes, as a Proposed Tumor Suppressor Autophagic Cell Death Related Genes, Can Be Targeted by Antidiabetic Therapy in Nondiabetic Breast Cancer Patients

Abstract

Introduction Breast cancer can be treated effectively with personalized, gene-targeted therapies due to its molecular and genetic differences. Our study aims to identify breast cancer-specific tumor suppressor genes related to autophagic cell death and discover new drugs that target these mechanisms, even if they are not breast cancer-specific. Materials and methods Gene intensity values of 457 tumor and 19 healthy breast tissues were used to determine downregulated and upregulated genes related to autophagy and apoptosis using Bioconductor R program via LIMMA package. Then, genes affecting survival were identified by survival analysis via Kaplan-Meier Plotter tool. Furthermore, the signalling pathways associated with these genes and targeting candidate drug components were determined by gene enrichment analysis using "KEGG pathway option" and Drug MATADOR in "ShinyGo 0.82" web-tool, respectively. Results Breast cancer tumor tissues showed downregulation of genes related to autophagy and apoptosis (c19orf12, CRYAB, LEP, SRPX, SNCA, FOXO1) and upregulation of others (SLC7A5, ATP2A2, INHBA, ATP5IF1). Among these, SLC7A5, c19orf12, LEP, SPRX, SNCA, and FOXO1 affected patient survival and prognosis. The AMPK signaling pathway, targeting FOXO1 and LEP, was identified as key. Only the LEP gene was targeted by Metformin, Pioglitazone, Rosiglitazone, and Troglitazone. Conclusion In our study, survival associated LEP and FOXO1 genes were identified as candidate tumor suppressor genes associated with autophagic cell death in non-obese and non-diabetic breast cancer patients. Anti-diabetic drugs such as Metformin, Pioglitazone, Rosiglitazone, Troglitazone are proposed as candidate components in the treatment processes by targeting the LEP gene in nondiabetic breast cancer patients.