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

: 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 pathogenic variants (PVs) on the tumour microenvironment. Additionally, while the genetic basis of PV breast cancer is well-studied, the role of epigenetic mediators in the tumourigenesis of these hereditary breast cancers is also worth exploring. : PVs in the gene interact with stromal cells and immune cells, promoting epithelial-mesenchymal transition, angiogenesis, and affecting oestrogen levels. Additionally, 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 and, to a lesser extent, genes. The upregulation of LSD-1 is generally associated with a poorer prognosis in cancer patients. In the context of breast cancer in PV carriers, LSD-1 contributes to tumour development through various mechanisms. These include the maintenance of a hypoxic environment and direct suppression of gene expression. : While LSD-1 itself does not directly cause mutations in or 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 PVs. Targeting LSD-1 may help counteract its detrimental effects and provide a promising avenue for therapy in this specific subgroup of breast cancer.