Publication: Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer.
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Identifiers
Date
2016
Authors
Gasca, Jessica
Flores, Maria Luz
Giráldez, Servando
Ruiz-Borrego, Manuel
Tortolero, María
Romero, Francisco
Japón, Miguel A
Sáez, Carmen
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
FBXW7 is a component of SCF (complex of SKP1, CUL1 and F-box-protein)-type ubiquitin ligases that targets several oncoproteins for ubiquitination and degradation by the proteasome. FBXW7 regulates cellular apoptosis by targeting MCL1 for ubiquitination. Recently, we identified PLK1 as a new substrate of FBXW7 modulating the intra-S-phase DNA-damage checkpoint. Taxanes are frequently used in breast cancer treatments, but the acquisition of resistance makes these treatments ineffective. We investigated the role of FBXW7 and their substrates MCL1 and PLK1 in regulating the apoptotic response to paclitaxel treatment in breast cancer cells and their expression in breast cancer tissues. Paclitaxel-sensitive MDA-MB-468 and a paclitaxel-resistant MDA-MB-468R subclone were used to study the role of FBXW7 and substrates in paclitaxel-induced apoptosis. Forced expression of FBXW7 or downregulation of MCL1 or PLK1 restored sensitivity to paclitaxel in MDA-MB-468R cells. By contrary, FBXW7-silenced MDA-MB-468 cells became resistant to paclitaxel. The expression of FBXW7 and substrates were studied in 296 invasive carcinomas by immunohistochemistry and disease-free survival was analyzed in a subset of patients treated with paclitaxel. In breast cancer tissues, loss of FBXW7 correlated with adverse prognosis markers and loss of FBXW7 and MCL1 or PLK1 accumulation were associated with diminished disease-free survival in paclitaxel-treated patients. We conclude that FBXW7 regulates the response to paclitaxel by targeting MCL1 and PLK1 in breast cancer cells and thus targeting these substrates may be a valuable adjunct for paclitaxel treatment. Also, FBXW7, MCL1 and PLK1 may be relevant predictive markers of tumor progression and response to paclitaxel treatment.
Description
MeSH Terms
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Breast Neoplasms
Cell Cycle
Cell Cycle Proteins
Cell Line, Tumor
Drug Resistance, Neoplasm
F-Box-WD Repeat-Containing Protein 7
Female
Humans
Kaplan-Meier Estimate
MCF-7 Cells
Myeloid Cell Leukemia Sequence 1 Protein
Paclitaxel
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins
RNA Interference
Apoptosis
Breast Neoplasms
Cell Cycle
Cell Cycle Proteins
Cell Line, Tumor
Drug Resistance, Neoplasm
F-Box-WD Repeat-Containing Protein 7
Female
Humans
Kaplan-Meier Estimate
MCF-7 Cells
Myeloid Cell Leukemia Sequence 1 Protein
Paclitaxel
Protein Serine-Threonine Kinases
Proto-Oncogene Proteins
RNA Interference
DeCS Terms
CIE Terms
Keywords
FBXW7, MCL1, PLK1, Pathology Section, apoptosis, paclitaxel