Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple-negative breast and serous ovarian cancers

N. J. Birkbak, Y. Li, S. Pathania, A. Greene-Colozzi, M. Dreze, C. Bowman-Colin, Z. Sztupinszki, M. Krzystanek, M. Diossy, N. Tung, P. D. Ryan, J. E. Garber, D. P. Silver, J. D. Iglehart, Z. C. Wang, D. Szuts, Zoltan Szallasi, A. L. Richardson

Research output: Contribution to journalArticle

Abstract

Background: Platinum-based therapy is an effective treatment for a subset of triple-negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. Patients and methods: We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared with resistant triple-negative breast cancers in two independent neoadjuvant cisplatin-treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. Results: We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum-sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin but has no effect on paclitaxel sensitivity. Conclusions: A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple-negative breast cancer and ovarian cancer.

Original languageEnglish (US)
Pages (from-to)903-909
Number of pages7
JournalAnnals of Oncology
Volume29
Issue number4
DOIs
StatePublished - Apr 1 2018
Externally publishedYes

Keywords

  • Gene expression-based predictor of treatment sensitivity
  • Ovarian cancer
  • Platinum-based chemotherapy
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Hematology
  • Oncology

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  • Cite this

    Birkbak, N. J., Li, Y., Pathania, S., Greene-Colozzi, A., Dreze, M., Bowman-Colin, C., Sztupinszki, Z., Krzystanek, M., Diossy, M., Tung, N., Ryan, P. D., Garber, J. E., Silver, D. P., Iglehart, J. D., Wang, Z. C., Szuts, D., Szallasi, Z., & Richardson, A. L. (2018). Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple-negative breast and serous ovarian cancers. Annals of Oncology, 29(4), 903-909. https://doi.org/10.1093/annonc/mdy049