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Signaling Pathways in Disease · Journal article
Journal of Biomedical Science · August 11, 2026
Raises a question worth testing. It does not answer one.
This is a mechanistic and preclinical investigation showing that the long non-coding RNA Smyca promotes homologous recombination and immune evasion in triple-negative breast cancer through a complex with FOXM1, and that targeting this axis sensitizes TNBC to chemotherapy, PARP inhibitors, and enhances anti-tumor immunity in cell and mouse models. Clinical significance is suggested by correlative analysis of patient expression data but remains unproven in prospective trials.
Mechanistic and preclinical study using in vitro assays, patient-derived organoids, xenograft and syngeneic mouse models, and observational patient expression analysis. TNBC cell lines, patient-derived organoids, xenograft and syngeneic mouse models, and breast cancer patient cohorts for expression correlation. Intervention: Smyca ablation, targeting of Smyca-FOXM1 complex, Smyca-targeting antisense oligonucleotides delivered by nanoparticle, in combination with platinum or PARP inhibitors. Compared with: Control (non-targeted or vehicle-treated) models and patient cohorts stratified by Smyca expression and HR status.
Smyca is highly expressed in TNBC and is induced by genotoxic agents to enhance HR repair Smyca binds FOXM1 and recruits it to promoters of HR and nucleotide metabolism genes Smyca ablation induces BRCAness in HR-proficient TNBC, sensitizing to platinum or PARPi
Safety was not reported in the material analysed. Check the source before drawing any conclusion about harm.
The findings propose Smyca as a potential therapeutic target to overcome PARPi resistance and enhance immunotherapy in HR-proficient TNBC, but these conclusions rest on preclinical evidence and observational correlations in patient samples. Translation to clinical benefit requires prospective validation in human trials.
Mechanistic discovery study using cell assays, organoid and mouse models identifying Smyca-FOXM1 as a potential target, without clinical trial data or hard clinical outcomes to support therapeutic claims.
As stated by the source record.
The findings propose Smyca as a potential therapeutic target to overcome PARPi resistance and enhance immunotherapy in HR-proficient TNBC, but these conclusions rest on preclinical evidence and observational correlations in patient samples. Translation to clinical benefit requires prospective validation in human trials.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
What is missing. This record has no reported figures. That is a gap in the analysis, not a judgement about the study.
Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options. Although PARP inhibitor (PARPi) offers great promise in treating TNBC with deficiency in homologous recombination (HR), most TNBC patients are HR-proficient. Furthermore, acquired resistance to PARPi remains as a challenge. Thus, there is an unmet need to identify new therapeutic target for developing advanced TNBC treatment strategy. Methods I-SceI reporter assay and alkaline comet assay were used to analyze the role of Smyca in HR repair. Ingenuity pathway analysis was used to identify upstream regulators of Smyca -regulated transcriptome. RNA immunoprecipitation and RNA pull down were used to examine Smyca -FOXM1 interaction. Chromatin immunoprecipitation followed by sequencing was performed to identify FOXM1 target genes that are regulated by Smyca. Chromatin isolation by RNA purification was used to determine Smyca loading onto the promoters of FOXM1 target genes. Patient-derived organoid and xenograft mouse models were performed to evaluate the effect of Smyca on chemoresistance. Nanoparticle-assisted gapmer antisense oligonucleotides delivery was used to target Smyca in vivo. Co-culture of CD3 + T cells with TNBC cells and syngeneic mouse model were used to examine the effect of Smyca -FOXM1 targeting on anti-tumor immunity. Results The long non-coding RNA Smyca is highly expressed in TNBC. We show that Smyca is induced by genotoxic agents to enhance HR repair. Mechanistically, Smyca binds FOXM1 and promotes the recruitment of FOXM1 to the promoters of a set of HR and nucleotide metabolism genes, thereby promoting their expression. Smyca ablation induces BRCAness in HR-proficient TNBC, thereby sensitizing these tumors to platinum or PARPi. Furthermore, targeting Smyca -FOXM1 complex in combination with platinum or PARPi 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. Conclusions Our study identifies an unprecedented role of Smyca in HR repair to promote TNBC survival and immune evasion in response to therapy and suggests Smyca as a potential target for sensitizing TNBC to chemotherapy, PARPi, or immunotherapy.
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