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NCAPH drives breast cancer progression and identifies a gene signature that predicts luminal a tumour recurrence.

  • Mendiburu-Eliçabe, Marina
  • García-Sancha, Natalia
  • Corchado-Cobos, Roberto
  • Martínez-López, Angélica
  • Chang, Hang
  • Hua Mao, Jian
  • Blanco-Gómez, Adrián
  • García-Casas, Ana
  • Castellanos-Martín, Andrés
  • Salvador, Nélida
  • Jiménez-Navas, Alejandro
  • Pérez-Baena, Manuel
  • Sánchez-Martín, Manuel
  • Abad-Hernández, María
  • Carmen, Sofía
  • Claros-Ampuero, Juncal
  • Cruz-Hernández, Juan
  • Rodríguez-Sánchez, César
  • García-Cenador, María
  • García-Criado, Francisco
  • And 3 more
Publication Date
Feb 01, 2024
eScholarship - University of California
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BACKGROUND: Luminal A tumours generally have a favourable prognosis but possess the highest 10-year recurrence risk among breast cancers. Additionally, a quarter of the recurrence cases occur within 5 years post-diagnosis. Identifying such patients is crucial as long-term relapsers could benefit from extended hormone therapy, while early relapsers might require more aggressive treatment. METHODS: We conducted a study to explore non-structural chromosome maintenance condensin I complex subunit Hs (NCAPH) role in luminal A breast cancer pathogenesis, both in vitro and in vivo, aiming to identify an intratumoural gene expression signature, with a focus on elevated NCAPH levels, as a potential marker for unfavourable progression. Our analysis included transgenic mouse models overexpressing NCAPH and a genetically diverse mouse cohort generated by backcrossing. A least absolute shrinkage and selection operator (LASSO) multivariate regression analysis was performed on transcripts associated with elevated intratumoural NCAPH levels. RESULTS: We found that NCAPH contributes to adverse luminal A breast cancer progression. The intratumoural gene expression signature associated with elevated NCAPH levels emerged as a potential risk identifier. Transgenic mice overexpressing NCAPH developed breast tumours with extended latency, and in Mouse Mammary Tumor Virus (MMTV)-NCAPHErbB2 double-transgenic mice, luminal tumours showed increased aggressiveness. High intratumoural Ncaph levels correlated with worse breast cancer outcome and subpar chemotherapy response. A 10-gene risk score, termed Gene Signature for Luminal A 10 (GSLA10), was derived from the LASSO analysis, correlating with adverse luminal A breast cancer progression. CONCLUSIONS: The GSLA10 signature outperformed the Oncotype DX signature in discerning tumours with unfavourable outcomes, previously categorised as luminal A by Prediction Analysis of Microarray 50 (PAM50) across three independent human cohorts. This new signature holds promise for identifying luminal A tumour patients with adverse prognosis, aiding in the development of personalised treatment strategies to significantly improve patient outcomes.

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