Regulation of antiviral and antitumor immunity by the <i>BRCA1</i> pseudogene in human cancers.

Abstract

Pseudogenes have been regarded as nonfunctional byproducts of evolutionary processes. However, emerging evidence indicates that pseudogenes perform diverse biological roles in human physiology and pathology. We identified the <i>BRCA1</i> pseudogene (<i>BRCA1P1</i>), a fusion pseudogene derived from the <i>BRCA1</i> tumor suppressor and <i>RPLP1</i> ribosomal protein genes, as an immunoregulatory RNA in breast cancer. In this study, we show that <i>BRCA1P1</i> expression varies across multiple cancer cell types, with no significant association with <i>BRCA1</i> or <i>BRCA2</i> somatic mutations in breast and ovarian tumors. Interestingly, <i>BRCA1P1</i> inhibition elicits antitumor effects in multiple cancer cell types and preclinical tumor models through an antiviral defense mechanism. Loss of <i>BRCA1P1</i> induces antiviral gene expression, promotes apoptosis, and increases sensitivity to chemotherapy in various cancer cells, without inducing apoptosis in nonmalignant cells. This antiviral response also enhances macrophage-mediated phagocytosis of <i>BRCA1P1</i>-deficient cancer cells. Mechanistically, the majority of <i>BRCA1P1</i> transcripts are circular RNAs and regulate NF-κB-driven antiviral gene expression. Furthermore, intratumoral expression of <i>BRCA1P1</i> is elevated in tumor cells, compared to normal breast tissue, and its depletion significantly inhibits the growth of both primary and metastatic breast tumor organoids. Finally, in a humanized mouse model of breast cancer, <i>BRCA1P1</i> loss stimulates antiviral gene expression and increases T cell infiltration into tumors. These findings support a critical role for <i>BRCA1P1</i> in regulating innate immune defense and antitumor responses across cancer types, suggesting that targeting pseudogene-derived RNAs may offer innovative therapeutic strategies to enhance antitumor immunity in breast and other cancers.