The tumour microenvironment in BRCA1/BRCA2 hereditary breast cancer and the role of epigenetics in its regulation

Abstract

Hereditary genetic conditions such as the autosomal-dominant Hereditary Breast and Ovarian Cancer (HBOC) syndrome, in which genes such as _BRCA1_ and _BRCA2_ pathogenic variants (PVs) are inherited, greatly increase the risks of being diagnosed with breast cancer. Breast cancers in _BRCA1/2_ PV carriers tend to be more aggressive and have poorer prognoses in part because these PVs influence the tumour microenvironment and facilitate tumourigenesis through their interactions with stromal cells and immune cells, promoting epithelial-mesenchymal transition and angiogenesis, and influencing oestrogen levels. In addition, _BRCA1_ PVs also contribute to breast cancer by exerting epigenetic effects on cells, such as DNA methylation and histone acetylation, thereafter suppressing the expression of proto-oncogenes and promoting cytokine dysregulation. Amongst epigenetic regulators, lysine-specific demethylase 1 (LSD-1) has been touted to be a master epigenetic regulator of both transcription repression and activation, regulating both _BRCA1_ and, to a lesser extent, _BRCA2_ genes epigenetically. Upregulation of LSD-1 in cancer patients has generally been associated with a poorer prognosis, and LSD-1 contributes to the development of breast cancer in _BRCA1/2_ PV patients through a plethora of mechanisms, including the perpetuation of a hypoxic environment and through direct suppression of _BRCA1_ gene expression. While LSD1 has no direct role in mutations of _BRCA1_ or _BRCA2_ genes, its epigenetic influence shines light on the role of LSD1 inhibitors as a potential mode of therapy in the management of breast cancer, particularly for _BRCA1/2_ PV carriers.