In Vitro Models of Triple-Negative Breast Cancer of Sub-Saharan African Ancestry Suggest BLM-Centred DNA Damage Repair Dependency and Pevonedistat Sensitivity
9 affiliations
- 1i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
- 2IPATIMUP—Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-135 Porto, Portugal
- 3ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
- 4Research Center of IPO-Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)/Porto Comprehensive Cancer Center (P.CCC) Raquel Seruca, 4200-162 Porto, Portugal
- 5FP-I3ID—Instituto de Investigação, Inovação e Desenvolvimento da Fundação Fernando Pessoa , University Fernando Pessoa, 4200-253 Porto, Portugal
- 6Department of Surgical Oncology, Portuguese Oncology Institute of Porto, 4200-162 Porto, Portugal
- 7School of Medicine and Biomedical Sciences, University Fernando Pessoa, 4420-096 Gondomar, Portugal
- 8Instituto Superior Técnico (IST), Universidade de Lisboa, 1049-001 Lisboa, Portugal
- 9Instituto de Engenharia de Sistemas e Computadores—Investigação e Desenvolvimento (INESC-ID), 1000-029 Lisboa, Portugal
Abstract
Triple-negative breast cancer (TNBC) is more prevalent in women of sub-Saharan African (SSA) than European (EUR) ancestry. Despite ancestry-related heterogeneity remaining neglected in cancer research, its evaluation can reveal useful insights on essential pathways underlying complex diseases. High-throughput data (DepMap and GDSC) were mined by performing differential analyses (gene essentiality and drug sensitivity, respectively) between SSA and EUR TNBC cell lines. BLM and interacting genes (RMI1, RMI2, TOP3A) showed greater essentiality in SSA than in EUR TNBC cell lines. SSA TNBC patients and cancer cell lines tended to have a lower median BLM expression than EUR counterparts, and its expression was positively correlated with structural mutations in tumour cells. Concordantly, BLM expression was higher in TNBC tumour cells than in normal cells, suggesting activation due to accumulation of mutations, particularly in cancers with a high burden of structural mutations. SSA TNBC cell lines were also more sensitive to the drug Pevonedistat. Transcriptomic analyses revealed that in the drug-exposed condition, DNA damage repair and helicase-related pathways were significantly downregulated, in several of which BLM is a significant core gene. Our findings support incorporating ancestry into oncobiology in vitro modelling and conducting further studies to assess Pevonedistat as a potential TNBC treatment.
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BibTeX
@article{pinto2026vitro,
title = {{In Vitro Models of Triple-Negative Breast Cancer of Sub-Saharan African Ancestry Suggest BLM-Centred DNA Damage Repair Dependency and Pevonedistat Sensitivity}},
author = {Ricardo J. Pinto and Ana C. Magalhães and Clara M. Bento and Fernanda Rosário and Lúcio Lara Santos and Emanuel Gonçalves and Luisa Pereira},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219980},
url = {https://www.mdpi.com/1422-0067/27/21/9980},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - In Vitro Models of Triple-Negative Breast Cancer of Sub-Saharan African Ancestry Suggest BLM-Centred DNA Damage Repair Dependency and Pevonedistat Sensitivity
AU - Ricardo J. Pinto
AU - Ana C. Magalhães
AU - Clara M. Bento
AU - Fernanda Rosário
AU - Lúcio Lara Santos
AU - Emanuel Gonçalves
AU - Luisa Pereira
PY - 2026
DA - 2026/11/07
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219980
UR - https://www.mdpi.com/1422-0067/27/21/9980
AB - Triple-negative breast cancer (TNBC) is more prevalent in women of sub-Saharan African (SSA) than European (EUR) ancestry. Despite ancestry-related heterogeneity remaining neglected in cancer research, its evaluation can reveal useful insights on essential pathways underlying complex diseases. High-throughput data (DepMap and GDSC) were mined by performing differential analyses (gene essentiality and drug sensitivity, respectively) between SSA and EUR TNBC cell lines. BLM and interacting genes (RMI1, RMI2, TOP3A) showed greater essentiality in SSA than in EUR TNBC cell lines. SSA TNBC patients and cancer cell lines tended to have a lower median BLM expression than EUR counterparts, and its expression was positively correlated with structural mutations in tumour cells. Concordantly, BLM expression was higher in TNBC tumour cells than in normal cells, suggesting activation due to accumulation of mutations, particularly in cancers with a high burden of structural mutations. SSA TNBC cell lines were also more sensitive to the drug Pevonedistat. Transcriptomic analyses revealed that in the drug-exposed condition, DNA damage repair and helicase-related pathways were significantly downregulated, in several of which BLM is a significant core gene. Our findings support incorporating ancestry into oncobiology in vitro modelling and conducting further studies to assess Pevonedistat as a potential TNBC treatment.
SN - 1422-0067
ER -