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

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.

• Authors: 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, Z Szallasi, A L Richardson
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 29 Issue 4 Pg. 903-909 (04 01 2018) ISSN: 1569-8041 [Electronic] England
• PMID: 29452344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Platinum Compounds
• Bloom syndrome protein
• RecQ Helicases

Topics

• Antineoplastic Agents (therapeutic use)
• DNA Damage
• Female
• Humans
• Ovarian Neoplasms (genetics, metabolism, pathology)
• Platinum Compounds (therapeutic use)
• RecQ Helicases (physiology)
• Triple Negative Breast Neoplasms (drug therapy, genetics, metabolism, pathology)