title: Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer.
abstract: Molecular characterization of radical prostatectomy specimens after systemic therapy may identify a gene expression profile for resistance to therapy. This study assessed tumor cells from patients with prostate cancer participating in a phase II neoadjuvant docetaxel and androgen deprivation trial to identify mediators of resistance. Transcriptional level of 93 genes from a docetaxel-resistant prostate cancer cell lines microarray study was analyzed by TaqMan low-density arrays in tumors from patients with high-risk localized prostate cancer (36 surgically treated, 28 with neoadjuvant docetaxel + androgen deprivation). Gene expression was compared between groups and correlated with clinical outcome. VIM, AR and RELA were validated by immunohistochemistry. CD44 and ZEB1 expression was tested by immunofluorescence in cells and tumor samples. Parental and docetaxel-resistant castration-resistant prostate cancer cell lines were tested for epithelial-to-mesenchymal transition (EMT) markers before and after docetaxel exposure. Reversion of EMT phenotype was investigated as a docetaxel resistance reversion strategy. Expression of 63 (67.7%) genes differed between groups (P < 0.05), including genes related to androgen receptor, NF-κB transcription factor, and EMT. Increased expression of EMT markers correlated with radiologic relapse. Docetaxel-resistant cells had increased EMT and stem-like cell markers expression. ZEB1 siRNA transfection reverted docetaxel resistance and reduced CD44 expression in DU-145R and PC-3R. Before docetaxel exposure, a selected CD44(+) subpopulation of PC-3 cells exhibited EMT phenotype and intrinsic docetaxel resistance; ZEB1/CD44(+) subpopulations were found in tumor cell lines and primary tumors; this correlated with aggressive clinical behavior. This study identifies genes potentially related to chemotherapy resistance and supports evidence of the EMT role in docetaxel resistance and adverse clinical behavior in early prostate cancer.
authors.affiliation: Authors' Affiliations: Laboratory of Translational Oncology and Medical Oncology Department; Bioinformatics Platform Department, Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Laboratory and Department of Urology, Hospital Clínic, Barcelona; Department of Pathology, Hospital Clínic, Universitat de Barcelona; Althia; Tumor Bank, Hospital Clínic-IDIBAPS Biobank, Barcelona; Medical Oncology Department, Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; and Medical Oncology Department, Hospital Parc Taulí, Sabadell, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Marín-Aguilera
authors.forename: Jordi
authors.initials: J
authors.lastname: Codony-Servat
authors.forename: Òscar
authors.initials: Ò
authors.lastname: Reig
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lozano
authors.forename: Pedro Luis
authors.initials: PL
authors.lastname: Fernández
authors.forename: María Verónica
authors.initials: MV
authors.lastname: Pereira
authors.forename: Natalia
authors.initials: N
authors.lastname: Jiménez
authors.forename: Michael
authors.initials: M
authors.lastname: Donovan
authors.forename: Pere
authors.initials: P
authors.lastname: Puig
authors.forename: Lourdes
authors.initials: L
authors.lastname: Mengual
authors.forename: Raquel
authors.initials: R
authors.lastname: Bermudo
authors.forename: Albert
authors.initials: A
authors.lastname: Font
authors.forename: Enrique
authors.initials: E
authors.lastname: Gallardo
authors.forename: María José
authors.initials: MJ
authors.lastname: Ribal
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcaraz
authors.forename: Pere
authors.initials: P
authors.lastname: Gascón
authors.forename: Begoña
authors.initials: B
authors.lastname: Mellado
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D043823:Taxoids / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D016896:Treatment Outcome; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; D043823:Taxoids; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000077143:Docetaxel