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Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Docetaxel response in BRCA1,p53-deficient mammary tumor cells is affected by Huntingtin and BAP1
Martín González-Fernández1,2, Carmen Perry1,2, Nora Merete Gerhards1
1Department of Infectious Diseases and Pathobiology, Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
Abstract:
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.
Insights
Huntingtin (HTT) loss sensitizes BRCA1-deficient breast cancer cells to docetaxel by affecting mitotic spindles. BAP1 depletion protects these cells, offering new therapeutic targets for triple-negative breast cancer (TNBC).
Area of Science:
- Oncology
- Cell Biology
- Genetics
Background:
- Taxanes are chemotherapy drugs that induce mitotic errors, crucial for cancer cell death.
- Chromosomal instability (CIN) is a hallmark of cancers like BRCA1-deficient triple-negative breast cancer (TNBC).
- Understanding docetaxel's mechanism in BRCA1-deficient TNBC is vital for targeted therapies.
Purpose of the Study:
- To investigate the mechanisms of docetaxel-induced cytotoxicity in BRCA1-deficient TNBC.
- To identify genes mediating docetaxel response in chromosomally unstable (CIN+) cells.
- To explore the roles of Huntingtin (HTT) and BRCA1-associated protein-1 (BAP1) in BRCA1-deficient CIN+ cells.
Main Methods:
- Functional genetic screens were performed in CIN+ cells to identify docetaxel response genes.
- Genetically engineered mouse mammary tumor cells (Brca1-/-;p53+/-) were used to model human BRCA1-deficient TNBC.
- The impact of HTT loss and BAP1 depletion on mitotic spindle dynamics and centrosome clustering was analyzed.
Main Results:
- Loss of HTT sensitized BRCA1-deficient mammary tumor cells to docetaxel by shortening mitotic spindle poles and increasing multipolarity.
- BAP1 depletion protected these cells from spindle aberrations, restoring spindle length and enhancing centrosome clustering.
- An interaction between HTT and BAP1 was identified in the context of docetaxel response.
Conclusions:
- HTT and BAP1 play critical roles in regulating mitotic spindle multipolarity and centrosome clustering in BRCA1-deficient cells.
- These findings highlight the influence of HTT and BAP1 on cellular response to microtubule-targeting agents.
- Targeting the interaction of HTT and BAP1 with the mitotic spindle may offer novel therapeutic strategies for BRCA1-deficient TNBC.
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