The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer.

Autor: Forte L; Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Turdo F; Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Ghirelli C; Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Aiello P; Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Casalini P; Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Iorio MV; Start Up Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., D'Ippolito E; Start Up Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Gasparini P; Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Agresti R; Division of Surgical Oncology, Breast Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Belmonte B; Tumor Immunology Unit, Department of Health, Human Pathology Section, University of Palermo, Palermo, Italy., Sozzi G; Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Sfondrini L; Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, via Mangiagalli 31, 20133, Milan, Italy., Tagliabue E; Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy. elda.tagliabue@istitutotumori.mi.it., Campiglio M; Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy., Bianchi F; Molecular Targeting Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.; Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, via Mangiagalli 31, 20133, Milan, Italy.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2018 May 23; Vol. 18 (1), pp. 586. Date of Electronic Publication: 2018 May 23.
DOI: 10.1186/s12885-018-4500-9
Abstrakt: Background: CDCP1, a transmembrane protein with tumor pro-metastatic activity, was recently identified as a prognostic marker in TNBC, the most aggressive breast cancer subtype still lacking an effective molecular targeted therapy. The mechanisms driving CDCP1 over-expression are not fully understood, although several stimuli derived from tumor microenvironment, such as factors present in Wound Healing Fluids (WHFs), reportedly increase CDCP1 levels.
Methods: The expression of CDCP1, PDGFRβ and ERK1/2cell was tested by Western blot after stimulation of MDA-MB-231 cells with PDGF-BB and, similarly, in presence or not of ERK1/2 inhibitor in a panel of TNBC cell lines. Knock-down of PDGFRβ was established in MDA-MB-231 cells to detect CDCP1 upon WHF treatment. Immunohistochemical staining was used to detect the expression of CDCP1 and PDGFRβ in TNBC clinical samples.
Results: We discovered that PDGF-BB-mediated activation of PDGFRβ increases CDCP1 protein expression through the downstream activation of ERK1/2. Inhibition of ERK1/2 activity reduced per se CDCP1 expression, evidence strengthening its role in CDCP1 expression regulation. Knock-down of PDGFRβ in TNBC cells impaired CDCP1 increase induced by WHF treatment, highlighting the role if this receptor as a central player of the WHF-mediated CDCP1 induction. A significant association between CDCP1 and PDGFRβ immunohistochemical staining was observed in TNBC specimens, independently of CDCP1 gene gain, thus corroborating the relevance of the PDGF-BB/PDGFRβ axis in the modulation of CDCP1 expression.
Conclusion: We have identified PDGF-BB/PDGFRβ-mediated pathway as a novel player in the regulation of CDCP1 in TNCBs through ERK1/2 activation. Our results provide the basis for the potential use of PDGFRβ and ERK1/2 inhibitors in targeting the aggressive features of CDCP1-positive TNBCs.
Databáze: MEDLINE
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