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.
The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer / L. Forte, F. Turdo, C. Ghirelli, P. Aiello, P. Casalini, M. Iorio, E. D'Ippolito, P. Gasparini, R. Agresti, B. Belmonte, G. Sozzi, L. Sfondrini, E. Tagliabue, M. Campiglio, F. Bianchi. - In: BMC CANCER. - ISSN 1471-2407. - 18:1(2018 May 23).
|Titolo:||The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer|
BIANCHI, FRANCESCA (Ultimo)
|Parole Chiave:||CDCP1; ERK1/2; FISH; IHC; PDGF-BB; PDGFRβ; TNBC; Oncology; Genetics; Cancer Research|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore MED/06 - Oncologia Medica
|Data di pubblicazione:||23-mag-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1186/s12885-018-4500-9|
|Appare nelle tipologie:||01 - Articolo su periodico|