BORIS in Hormone-Driven Cancers: Epigenetic Reprogramming, Transcriptional Plasticity, and Therapeutic Implications

Hormone-driven cancers, including prostate, breast, endometrial and ovarian cancers are a leading cause of cancer-related mortality. Endocrine therapies targeting androgen receptor and oestrogen receptor/progesterone receptor signalling have improved outcomes, but acquired resistance arising through genetic and epigenetic mechanisms that bypass receptor dependence remains a major challenge. BORIS (Brother of the Regulator of Imprinted Sites), a CTCF paralogue, is a germline-restricted regulator that becomes aberrantly reactivated in cancer through promoter hypomethylation, p53 loss, and CTCF displacement. Once expressed, BORIS displaces CTCF at shared genomic binding sites, disrupts TAD boundaries and reprograms CTCF binding sites into alternative transcriptional start sites, through SRCAP-mediated H2A.Z deposition, to activate germline genes that sustain proliferation, and therapeutic resistance. BORIS expression correlates with poor prognosis in ovarian and endometrial cancers, associates with ER/PR levels in breast cancer, and correlates with Gleason score in prostate cancer. BORIS represses AR signalling in ovarian cancer and inversely correlates with receptor expression in endometrial cancer. Its cancer-testis antigen properties position BORIS as an immunotherapy target, with preclinical vaccine efficacy demonstrated in breast cancer models. This review synthesises disease-specific evidence positioning BORIS as a driver of transcriptional reprogramming and endocrine resistance, identifies current knowledge gaps, and discusses translational implications of targeting this pathway.