title: Loss of FBXW7 and accumulation of MCL1 and PLK1 promote paclitaxel resistance in breast cancer.
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.
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gasca
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.
authors.forename: Maria Luz
authors.initials: ML
authors.lastname: Flores
authors.affiliation: Department of Microbiology, Faculty of Biology, Universidad de Sevilla, Seville, Spain.
authors.forename: Servando
authors.initials: S
authors.lastname: Giráldez
authors.affiliation: Oncology Unit, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ruiz-Borrego
authors.affiliation: Department of Microbiology, Faculty of Biology, Universidad de Sevilla, Seville, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Tortolero
authors.affiliation: Department of Microbiology, Faculty of Biology, Universidad de Sevilla, Seville, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Romero
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.|Department of Pathology, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Japón
authors.affiliation: Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain.|Department of Pathology, Hospital Universitario Virgen del Rocío, Seville, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sáez
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D017239:Paclitaxel; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C513273:FBXW7 protein, human; C579095:MCL1 protein, human
keywords: FBXW7; MCL1; PLK1; Pathology Section; apoptosis; paclitaxel