Cancer-Associated Fibroblasts: Epigenetic Regulation and Therapeutic Intervention in Breast Cancer

SIMPLE SUMMARY: Drug resistance and insensitivity to treatments are the main challenges in breast cancer therapy. Cancer-associated fibroblasts (CAFs) are heterogeneous stromal cells with prevailing roles in cancer development and progression. Epigenetic alterations are essential in regulating CAF activation and heterogeneity. These modifications are druggable targets that can be reversed using pharmacological interventions. CAFs therefore, have a remarkable potential as a therapeutic target in breast cancer. This review provides an update on the mechanisms of epigenetic modulation in breast cancer and discusses the challenges of translating the optimism of CAF-directed therapies from bench to clinic. ABSTRACT: Breast cancer is the leading cause of cancer-related mortality in women worldwide. Cancer-associated fibroblasts (CAFs) are a heterogeneous population of cells in the solid tumour microenvironment. These cells are positively linked to breast cancer progression. Breast CAFs can be categorised into distinct subtypes according to their roles in breast carcinogenesis. Epigenetic modifications change gene expression patterns as a consequence of altered chromatin configuration and DNA accessibility to transcriptional machinery, without affecting the primary structure of DNA. Epigenetic dysregulation in breast CAFs may enhance breast cancer cell survival and ultimately lead to therapeutic resistance. A growing body of evidence has described epigenetic modulators that target histones, DNA, and miRNA as a promising approach to treat cancer. This review aims to summarise the current findings on the mechanisms involved in the epigenetic regulation in breast CAFs and discusses the potential therapeutic strategies via targeting these factors.