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 loss of CTCF-mediated repression. Once expressed, BORIS occupies CTCF sites, displacing or co-occupying them with CTCF, and reprograms clustered sites into alternative transcriptional start sites through SRCAP-mediated H2A.Z deposition, activating 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 the 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.