Identification of Key Genes and Pathways Associated with Adriamycin Resistance in Breast Cancer

Abstract

Objective: Drug resistance to the chemotherapeutic drug Adriamycin (ADR) is a key clinical impediment to successful breast cancer treatment (BrCa). However, the molecular mechanism and targets that mediate ADR resistance remain unclear. Therefore, the identification of ADR response biomarkers to improve the treatment of patients with BrCa is an urgent issue. Methods: The GSE24460 dataset on Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/) was employed in this investigation, which covers gene expression profiles of parental and ADR-resistant cell lines of MCF-7 (cell lines in the human breast cancer). Differentially expressed genes (DEGs) in parental and ADR-resistant cells, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway studies, and the interactions of protein-protein were used to identify the overall biological alterations (PPIs). The most prevalent DEGs in the PPI, GO, and KEGG pathways were discovered and using GSE34138 dataset from the GEO database were validated, and their ability to forecast overall survival (OS) and relapse-free survival (RFS) was clinically validated. The link between the DEGs and OS/RFS was studied after further verification of the most common DEGs in those pathways. The most significant crucial gene, collagen type-IV alpha 1 (COL4A1), was discovered in the MCF-7 and MCF-7/ADR cells using the quantitative real-time reverse transcription PCR, Western blot, and Cell Counting Kit-8 assays to further highlight the distinctions. Results: 207 DEGs in total were discovered, with 111 upregulated and 96 downregulated. After mapping the GOs, pathways, and PPI networks, six genes—cyclin-dependent kinase inhibitor 2A (CDKN2A), retinoblastoma 1 (RB1), C-X-C motif ligand 12 (CXCL12), COL4A1, intercellular cell molecule-1 of adhesion (ICAM1), and cadherin 1 (CDH1)—were found to be frequently enriched. COL4A1 was found to be favorably associated with ADR resistance and poor OS, as well as strongly associated with RFS. The correlation between CDH1 and ADR resistance was negative, which was substantial in terms of poor RFS. In MCF-7/ADR cells, COL4A1 also expression was noted to have increased, and COL4A1 knockdown significantly reduced the inhibitory concentration 50% value of ADR in those cells. Conclusions: Our data identified the significant pathways and genes for predicting the emergence of ADR resistance and revealed that COL4A1 regulated the proliferation of MCF-7/ADR and played a crucial role in ADR resistance. Therefore, COL4A1 shows that it can be novel target for improving patients prognosis with ADR-resistant BrCa.