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

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.

Keywords: DNA methylation; breast cancer; cancer-associated fibroblasts; epigenetic; heterogeneity; miRNA dysregulation; post-translational modification.

Figure 1

Tumour microenvironment and the origin of CAFs. (a) Cellular and non-cellular components in the tumour microenvironment comprising of fibroblasts, adipocytes, macrophages, endothelial cells and the extracellular matrix. (b) CAFs may originate from normal resident fibroblasts, mesenchymal stem cells, epithelial cells, endothelial cells, vascular smooth muscle cells, pericytes, adipocytes and/or bone marrow fibrocytes.

Figure 2

Reprogramming of NFs into CAFs through epigenetic regulation. Fibroblast activating factor secreted by the tumour cells or CAFs caninduced transformation of the normal resident fibroblast into CAFs through epigenetic modulation, and subsequently support tumour progression.