Molecular determinants of neoadjuvant chemotherapy resistance in breast cancer: An analysis of gene expression and
Hedda Michelle Guevara-Nieto1,2,3, Carlos A Orozco-Castaño1,2, Rafael Parra-Medina4,5
1Grupo de Investigación en Biología del Cáncer, Instituto Nacional de Cancerología, Bogotá, Colombia.
Abstract:
Neoadjuvant chemotherapy (NAC) is a critical component of breast cancer treatment, but the molecular mechanisms underlying resistance remain poorly understood. This study aimed to identify transcriptomic changes associated with NAC resistance across four breast cancer subtypes: Luminal A, Luminal B/HER2-positive, Luminal B/HER2-negative, and Triple-Negative Breast Cancer (TNBC). RNA-seq analysis was performed on paired pre- and post-NAC breast cancer samples from 32 non-responders. Differentially expressed genes (DEGs) were identified, and functional enrichment analyses were conducted. Protein-protein interaction (PPI) networks were constructed to identify hub genes. Tumor microenvironment (TME) infiltration was estimated using deconvolution algorithms. The results revealed distinct gene expression profiles between pre- and post-NAC samples, with FOS and NR4A1 being common DEGs across all subtypes. Enriched pathways varied among subtypes, including signal transduction, estrogen biosynthesis, extracellular matrix organization, dendritic cell activation, and B cell activation. TME analysis showed increased infiltration of specific immune cell populations after NAC, including CD4 memory T cells, regulatory T cells, neutrophils, macrophages, and mast cells, varying by subtype. These findings suggest that NAC modulates gene expression, cellular activity, and TME interactions, potentially contributing to treatment resistance. Understanding the molecular determinants of NAC resistance is crucial for developing targeted therapeutic strategies and improving outcomes for breast cancer patients.
Insights
Neoadjuvant chemotherapy resistance in breast cancer involves significant transcriptomic shifts and altered tumor microenvironments. Identifying key genes and pathways is crucial for developing new treatment strategies.
Area of Science:
- Oncology
- Genomics
- Immunology
Background:
- Neoadjuvant chemotherapy (NAC) is vital for breast cancer treatment.
- Molecular mechanisms of NAC resistance are not fully understood.
- Resistance impacts treatment efficacy across diverse breast cancer subtypes.
Purpose of the Study:
- Investigate transcriptomic alterations linked to NAC resistance.
- Analyze changes across Luminal A, Luminal B (HER2+/–), and Triple-Negative Breast Cancer (TNBC).
- Identify key genes, pathways, and tumor microenvironment (TME) modifications.
Main Methods:
- RNA-sequencing on paired pre- and post-NAC samples from 32 non-responders.
- Differential gene expression analysis and functional enrichment.
- Protein-protein interaction network construction and TME deconvolution.
Main Results:
- Distinct gene expression profiles pre- and post-NAC, with FOS and NR4A1 as common differentially expressed genes.
- Subtype-specific enriched pathways including signal transduction and immune cell activation.
- Increased infiltration of CD4 memory T cells, regulatory T cells, neutrophils, macrophages, and mast cells post-NAC.
Conclusions:
- NAC induces significant molecular and cellular changes in breast cancer, potentially driving resistance.
- Understanding these changes is key to developing targeted therapies for NAC resistance.
- Findings offer insights into improving treatment strategies and patient outcomes.
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