# Molecular determinants of neoadjuvant chemotherapy resistance in breast cancer: An analysis of gene expression and tumor microenvironment

## TL;DR

This study identifies gene expression changes and tumor microenvironment shifts linked to resistance to chemotherapy in breast cancer.

## Contribution

The study reveals subtype-specific gene expression profiles and TME infiltration patterns associated with neoadjuvant chemotherapy resistance.

## Key findings

- FOS and NR4A1 are common differentially expressed genes across all breast cancer subtypes.
- NAC treatment alters tumor microenvironment infiltration with immune cells like CD4 memory T cells and macrophages.
- Enriched pathways include signal transduction, estrogen biosynthesis, and extracellular matrix organization.

## 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.