The Tumour Microenvironment and Epigenetic Regulation in BRCA1 Pathogenic Variant-Associated Breast Cancers

Sep 22, 2026

BRCA1 pathogenic variant (PV)-associated breast cancers are frequently linked to hereditary HBOC syndrome and often show stronger aggressiveness and worse outcomes than sporadic cases. Although BRCA1 PV genetics are well characterized, epigenetic mechanisms shaping tumorigenesis remain critical. PVs act through stromal and immune interactions to drive EMT, angiogenesis, and altered oestrogen biology, while epigenetic control involves DNA methylation and histone acetylation. Lysine-specific demethylase 1 (LSD-1) functions as a master regulator over BRCA1 and partly BRCA2, promoting tumor development via hypoxia support and suppression of BRCA1 expression.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages19

Reading Time48 min

AccessFree to download

Introduction

BRCA1/BRCA2 in DNA repair and hereditary risk

Differences in tumour microenvironment and epigenetics

Results and Epigenetic Mechanisms

Interactions with stromal and immune cells

LSD-1 as a master epigenetic regulator

Therapeutic Implications

Potential of LSD-1 inhibitors

Review The Tumour Microenvironment and Epigenetic Regulation in BRCA1 Pathogenic Variant-Associated Breast Cancers Jun Yu Tay 1, Josh Xingchong Ho 1, Fan Foon Cheo 2 and Jabed Iqbal 2, * Citation: Tay, J.Y.; Ho, J.X.; Cheo, F.F.; Iqbal, J. The Tumour Microenvironment and Epigenetic Regulation in BRCA1 Pathogenic Variant-Associated Breast Cancers. Cancers 2024, 16, 3910 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers16233910 Academic Editor: Zhe Li Received: 3 October 2024 Revised: 9 November 2024 Accepted: 11 November 2024 Published: 21 November 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Lee Kong Chian School of Medicine, Imperial College London-Nanyang Technological University, Singapore 308232, Singapore 2 Department of Anatomical Pathology, Division of Pathology, Singapore General Hospital, Singapore 169856, Singapore * [Correspondence: jabed.iqbal@singhealth.com.sg](Correspondence: jabed.iqbal@singhealth.com.sg) Simple Summary: This review article sheds light on the differences in tumour microenvironment between sporadic breast cancers and BRCA1 and, to a lesser extent, BRCA2 pathogenic variant (PV)-associated breast cancers, which are usually hereditary. It also uncovers the epigenetic regulation behind the tumourigenesis and differences in tumour microenvironment, mainly exploring the role of the master epigenetic regulator, lysine-specific demethylase 1 (LSD-1) . Finally, it provides a gist of current therapeutics in the domain of hereditary breast cancer and includes recommendations for areas of further research into the topic. Abstract: Background/Objectives: BRCA1 pathogenic variant (PV)-associated breast cancers are most commonly seen in hereditary genetic conditions such as the autosomal-dominant Hereditary Breast and Ovarian Cancer (HBOC) syndrome, and rarely in sporadic breast cancer. Such breast cancers tend to exhibit greater aggressiveness and poorer prognoses due to the influence of BRCA1 pathogenic variants (PVs) on the tumour microenvironment. Additionally, while the genetic basis of BRCA1 PV breast cancer is well-studied, the role of epigenetic mediators in the tumourigenesis of these hereditary breast cancers is also worth exploring. Results: PVs in the BRCA1 gene interact with stromal cells and immune cells, promoting epithelial–mesenchymal transition, angiogenesis, and affecting oestrogen levels. Additionally, BRCA1 PVs contribute to breast cancer development through epigenetic effects on cells, including DNA methylation and histone acetylation, leading to the suppression of proto-oncogenes and dysregulation of cytokines. In terms of epigenetics, lysine-specific demethylase 1 (LSD-1) is considered a master epigenetic regulator, governing both transcriptional repression and activation. It exerts epigenetic control over BRCA1 and, to a lesser extent, BRCA2 genes. The upregulation of LSD-1 is generally associated with a poorer prognosis in cancer patients. In the context of breast cancer in BRCA1/2 PV carriers, LSD-1 contributes to tumour development through various mechanisms. These include the maintenance of a hypoxic environment and direct suppression of BRCA1 gene expression. Conclusions: While LSD-1 itself does not directly cause mutations in BRCA1 or BRCA2 genes, its epigenetic influence sheds light on the potential role of LSD-1 inhibitors as a therapeutic approach in managing breast cancer, particularly in individuals with BRCA1/2 PVs. Targeting LSD-1 may help counteract its detrimental effects and provide a promising avenue for therapy in this specific subgroup of breast cancer. Keywords: hereditary breast can

FAQs

What genetic context most commonly underlies BRCA1 PV-associated breast cancer?

BRCA1 PV-associated breast cancers are most commonly observed in hereditary conditions such as the autosomal-dominant HBOC syndrome, and are rarely sporadic.

How do BRCA1 pathogenic variants influence the tumour microenvironment?

BRCA1 PVs interact with stromal and immune cells, promoting processes such as epithelial–mesenchymal transition and angiogenesis, and affecting oestrogen levels.

Why is LSD-1 considered a key epigenetic regulator in this setting?

LSD-1 is described as a master epigenetic regulator controlling transcriptional repression and activation, with epigenetic control over BRCA1 and to a lesser extent BRCA2; its upregulation is generally linked to poorer prognosis.

Sep 22, 2026

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