Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 21, Pages 8671-8676Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0811835106
Keywords
chemotherapy; drug resistance
Categories
Funding
- Cancer Research UK
- Medical Research Council
- National Institutes of Health [NCI SPORE P50 CA 89393, R21LM008823-01A1]
- Breast Cancer Research Foundation
- Medical Research Council funded senior clinical research fellow
- MRC [G0701935] Funding Source: UKRI
- Cancer Research UK [19556] Funding Source: researchfish
- Medical Research Council [G0701935] Funding Source: researchfish
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Microtubule-stabilizing (MTS) agents, such as taxanes, are important chemotherapeutics with a poorly understood mechanism of action. We identified a set of genes repressed in multiple cell lines in response to MTS agents and observed that these genes are overexpressed in tumors exhibiting chromosomal instability (CIN). Silencing 22/50 of these genes, many of which are involved in DNA repair, caused cancer cell death, suggesting that these genes are involved in the survival of aneuploid cells. Overexpression of these CIN-survival'' genes is associated with poor outcome in estrogen receptor-positive breast cancer and occurs frequently in basal-like and Her2-positive cases. In diploid cells, but not in chromosomally unstable cells, paclitaxel causes repression of CIN-survival genes, followed by cell death. In the OV01 ovarian cancer clinical trial, a high level of CIN was associated with taxane resistance but carboplatin sensitivity, indicating that CIN may determine MTS response in vivo. Thus, pretherapeutic assessment of CIN may optimize treatment stratification and clinical trial design using these agents.
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