Docetaxel response in BRCA1,p53-deficient mammary tumor cells is affected by Huntingtin and BAP1

• 成果类型: Article
• 署名作者: Perry, Carmen; Gerhards, Nora Merete; Francica, Paola; Rottenberg, Sven; Nussenzweig, Andre
• 署名单位: University of Bern; University of Bern
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13627
• DOI: 10.1073/pnas
• 发表日期: 2024-12-24
• 关键词: prevents chromosome instability; gamma-tubulin; ubiquitin ligase; genetic screens; brca1; mouse; aurora; degradation; kinase; bard1

摘要

Taxanes are frequently used anticancer drugs known to kill tumor cells by inducing mitotic aberrations and segregation defects. A defining feature of specific cancers, notably triple- negative breast cancer (TNBC) and particularly those deficient in BRCA1, is chromosomal instability (CIN). Here, we focused on understanding the mechanisms of docetaxel- induced cytotoxicity, especially in the context of BRCA1- deficient TNBC. Using functional genetic screens in CIN+ cells, we identified genes that mediate docetaxel response and found an interaction between Huntingtin (HTT) and BRCA1-associated protein- 1 (BAP1). We employed Brca1-/-;p53-/- mammary tumor cells, derived from genetically engineered mouse tumors that closely mimic the human disease, to investigate the role of these genes in CIN+ BRCA1-deficient cells. Specifically, we observed that loss of HTT sensitizes CIN+ BRCA1- deficient mammary tumor cells to docetaxel by shortening mitotic spindle poles and increasing spindle multipolarity. In contrast, BAP1 depletion protected cells against these spindle aberrations by restoring spindle length and enhancing mitotic clustering of the extra centrosomes. In conclusion, our findings shed light on the roles of HTT and BAP1 in controlling mitotic spindle multipolarity and centrosome clustering, specifically in the absence of BRCA1. This affects the response to microtubule- targeting agents and suggests that further studies of the interaction of these genes with the mitotic spindle may provide useful insights into how to target CIN+ cells, particularly in the challenging therapeutic landscape of BRCA1- deficient TNBC.