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Smyca-FOXM1 ribonucleoprotein complex promotes homologous recombination and tumor immune evasion to define a therapeutic target of triple-negative breast cancer

ABSTRACT: Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options. We previously identified that the long noncoding RNA Smyca is highly expressed in TNBC to elicit multiple pro-tumor effects. Here, we show that Smyca is induced by DNA damage to enhance homologous recombination (HR) repair. Mechanistically, Smyca binds and guides FOXM1 to the promoters of a set of HR and nucleotide metabolism genes, thereby promoting their expression. Consequently, Smyca ablation induces BRCAness in HR-proficient TNBC, thereby sensitizing these tumors to platinum and PARP1 inhibitor (PARPi). Targeting Smyca/FOXM1 axis in combined with platinum or PARPi further activates cGAS/STING pathway and tumor immunogenicity to enhance anti-tumor immune surveillance. Clinically, Smyca expression in breast cancer patients correlates positively with therapy resistance and negatively with HR deficiency, interferon signature, and infiltration of anti-tumor immune cells. Our study identifies an unprecedented role of Smyca in HR repair to promote resistance to therapy and immune evasion during therapy and suggests Smyca as a potential target for sensitizing TNBC to chemotherapy, PARPi, or immune therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298060 | GEO | 2026/08/19

REPOSITORIES: GEO

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Smyca-FOXM1 ribonucleoprotein complex promotes homologous recombination and tumor immune evasion to define a therapeutic target of triple-negative breast cancer

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