Abstract
Simple SummaryDrug 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.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.
Highlights
Targeting stromal components in the tumour microenvironment (TME) is the latest hype in the cancer paradigm
Compared to mono-cultured breastbreast cancercancer (BC) cells, co-culture of BC cells and breast cancer-associated fibroblast (BCAF) increased the regulation of fibroblast-specific protein 1 (FSP1), TGF-β, PDGFβ, fibroblast growth factor 7 (FGF7), interleukins (IL-6 and IL-8), matrix metallopeptidases (MMP2 and MMP11), TIMP metallopeptidase inhibitor 1 (TIMP1), and vascular endothelial growth factor A (VEGFA)
These were the extracellular matrix (ECM)-cancer-associated fibroblasts (CAFs) with a demonstrated role in tissue remodelling, the inflammatory CAFs that are involved in immune modulation, and the contractile myofibroblasts which are responsible for cytoskeletal organisation [53]
Summary
Targeting stromal components in the tumour microenvironment (TME) is the latest hype in the cancer paradigm. Cancers 2020, 12, x fibroblasts (CAFs) which are highly implicated cancerimplicated pathogenesis [2]. CAFs within the tumour stroma that exhibit a thin, wavy, and elongated cruciform or stellate-shaped are fibroblast cells within the tumour stroma that exhibit a thin, wavy, and elongated cruciform or morphology harbouring specific biomarkers [3,4,5]. Compared to normal fibroblasts (NFs), CAFs are stellate-shaped morphology harbouring specific [3,4,5]. Compared to normal fibroblasts larger cells withare indented and possess a more basophilic cytoplasm thatbasophilic contains abundant rough (NFs), CAFs largernuclei cells with indented nuclei and possess a more cytoplasm that endoplasmic reticulum and free ribosomes, well-developed. Expression, addition to themutations absence of specific cancer mutations [7]
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