AsianScientist (Sept. 27, 2026) – Patients with triple-negative breast cancer (TNBC) have fewer treatment options to control its aggressive growth. TNBC tumours lack the molecular markers targeted by many other breast cancer drugs, leaving only chemotherapy as the standard treatment.
One promising targeted approach is the use of PARP inhibitors (PARPi). These drugs are particularly effective against tumours carrying mutations in genes such as BRCA1 and BRCA2, which can disrupt homologous recombination (HR), a DNA repair pathway. Blocking the DNA repair crew can cause cancer cells to accumulate too much DNA damage and die.
However, most TNBC patients still have functional HR and are therefore less likely to benefit from PARPi. Even patients whose tumours initially respond can develop resistance by restoring their ability to repair DNA.
To target this pathway and expand the use of targeted TNBC therapies, researchers at National Taiwan University, Academia Sinica, and Taipei Medical University in Taiwan explored Smyca, a long non-coding RNA (lncRNA) they had previously found to promote cancer. In their new study, published in the Journal of Biomedical Science, the team show how Smyca contributes to treatment resistance in TNBC by helping cancer cells recover from DNA-damaging therapies.
Unlike messenger RNAs which carry instructions for protein production, lncRNAs serve as coordinators of the genome by regulating how and when genes are turned on and off. TNBC cells express Smyca at high levels and the researchers found that its levels increase further in response to drugs like cisplatin and olaparib.
The team traced Smyca’s role in supporting the cancer cells’ DNA repair machinery. Through bioinformatics analysis and RNA-protein interaction experiments, they discovered that Smyca binds to the transcription factor FOXM1, a protein that controls the activity of several genes. Smyca guides FOXM1 to activate genes involved in different stages of HR, as well as nucleotide metabolism, which supplies the DNA building blocks needed to replicate and repair DNA.
True to this concept, blocking Smyca in HR-proficient TNBC cells, lab-grown patient-derived organoids and mouse models made the cancer cells more sensitive to both chemotherapy and PARPi treatments.
The researchers also found that losing Smyca helped expose the tumours to immune attack. Accumulated DNA damage activated the cGAS/STING pathway, an immune-sensing system that can send signals to recruit and activate immune cells against abnormal cells.
Together, these mechanisms suggest a possible way to extend the benefits of PARPi drugs beyond the smaller group of TNBC patients whose tumours are naturally HR-deficient.
“What makes this finding particularly important is that Smyca appears to connect two major mechanisms that allow tumours to survive from therapy, that is, DNA repair and immune escape,” said study co-author Ruey-Hwa Chen, a professor at the Institute of Biological Chemistry, Academia Sinica and Institute of Biochemical Sciences at National Taiwan University.
“By targeting this lncRNA pathway, we may be able to weaken the ability of tumours to repair treatment-induced DNA damage and simultaneously make them more exposed to the immune system.”
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Source: National Taiwan University ; Image: Eric Rodriguez/ Magnific
This article can be found at 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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