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

Luca Forte, Federica Turdo, Cristina Ghirelli, Piera Aiello, Patrizia Casalini, Marilena Valeria Iorio, Elvira D'Ippolito, Patrizia Gasparini, Roberto Agresti, Beatrice Belmonte, Gabriella Sozzi, Lucia Sfondrini, Elda Tagliabue, Manuela Campiglio, Francesca Bianchi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)586
JournalBMC Cancer
Volume18
Issue number1
DOIs
Publication statusPublished - May 23 2018

Fingerprint

Triple Negative Breast Neoplasms
MAP Kinase Signaling System
Wound Healing
Molecular Targeted Therapy
Staining and Labeling
Tumor Microenvironment
Proteins
Western Blotting
Breast Neoplasms
Cell Line
platelet-derived growth factor BB
Therapeutics
Genes
Neoplasms

Keywords

  • Antigens, CD/metabolism
  • Becaplermin/pharmacology
  • Cell Adhesion Molecules/metabolism
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Humans
  • MAP Kinase Signaling System/drug effects
  • Middle Aged
  • Mitogen-Activated Protein Kinase 1/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3/antagonists & inhibitors
  • Neoplasm Proteins/metabolism
  • RNA, Small Interfering/metabolism
  • Receptor, Platelet-Derived Growth Factor beta/genetics
  • Triple Negative Breast Neoplasms/genetics
  • Up-Regulation

Cite this

The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer. / Forte, Luca; Turdo, Federica; Ghirelli, Cristina; Aiello, Piera; Casalini, Patrizia; Iorio, Marilena Valeria; D'Ippolito, Elvira; Gasparini, Patrizia; Agresti, Roberto; Belmonte, Beatrice; Sozzi, Gabriella; Sfondrini, Lucia; Tagliabue, Elda; Campiglio, Manuela; Bianchi, Francesca.

In: BMC Cancer, Vol. 18, No. 1, 23.05.2018, p. 586.

Research output: Contribution to journalArticle

Forte, Luca ; Turdo, Federica ; Ghirelli, Cristina ; Aiello, Piera ; Casalini, Patrizia ; Iorio, Marilena Valeria ; D'Ippolito, Elvira ; Gasparini, Patrizia ; Agresti, Roberto ; Belmonte, Beatrice ; Sozzi, Gabriella ; Sfondrini, Lucia ; Tagliabue, Elda ; Campiglio, Manuela ; Bianchi, Francesca. / The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer. In: BMC Cancer. 2018 ; Vol. 18, No. 1. pp. 586.
@article{0d24c5ba3cf94c82bc031382c472274d,
title = "The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer",
abstract = "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.",
keywords = "Antigens, CD/metabolism, Becaplermin/pharmacology, Cell Adhesion Molecules/metabolism, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, MAP Kinase Signaling System/drug effects, Middle Aged, Mitogen-Activated Protein Kinase 1/antagonists & inhibitors, Mitogen-Activated Protein Kinase 3/antagonists & inhibitors, Neoplasm Proteins/metabolism, RNA, Small Interfering/metabolism, Receptor, Platelet-Derived Growth Factor beta/genetics, Triple Negative Breast Neoplasms/genetics, Up-Regulation",
author = "Luca Forte and Federica Turdo and Cristina Ghirelli and Piera Aiello and Patrizia Casalini and Iorio, {Marilena Valeria} and Elvira D'Ippolito and Patrizia Gasparini and Roberto Agresti and Beatrice Belmonte and Gabriella Sozzi and Lucia Sfondrini and Elda Tagliabue and Manuela Campiglio and Francesca Bianchi",
year = "2018",
month = "5",
day = "23",
doi = "10.1186/s12885-018-4500-9",
language = "English",
volume = "18",
pages = "586",
journal = "BMC Cancer",
issn = "1471-2407",
publisher = "BioMed Central Ltd.",
number = "1",

}

TY - JOUR

T1 - The PDGFRβ/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer

AU - Forte, Luca

AU - Turdo, Federica

AU - Ghirelli, Cristina

AU - Aiello, Piera

AU - Casalini, Patrizia

AU - Iorio, Marilena Valeria

AU - D'Ippolito, Elvira

AU - Gasparini, Patrizia

AU - Agresti, Roberto

AU - Belmonte, Beatrice

AU - Sozzi, Gabriella

AU - Sfondrini, Lucia

AU - Tagliabue, Elda

AU - Campiglio, Manuela

AU - Bianchi, Francesca

PY - 2018/5/23

Y1 - 2018/5/23

N2 - 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.

AB - 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.

KW - Antigens, CD/metabolism

KW - Becaplermin/pharmacology

KW - Cell Adhesion Molecules/metabolism

KW - Cell Line, Tumor

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Gene Knockdown Techniques

KW - Humans

KW - MAP Kinase Signaling System/drug effects

KW - Middle Aged

KW - Mitogen-Activated Protein Kinase 1/antagonists & inhibitors

KW - Mitogen-Activated Protein Kinase 3/antagonists & inhibitors

KW - Neoplasm Proteins/metabolism

KW - RNA, Small Interfering/metabolism

KW - Receptor, Platelet-Derived Growth Factor beta/genetics

KW - Triple Negative Breast Neoplasms/genetics

KW - Up-Regulation

U2 - 10.1186/s12885-018-4500-9

DO - 10.1186/s12885-018-4500-9

M3 - Article

VL - 18

SP - 586

JO - BMC Cancer

JF - BMC Cancer

SN - 1471-2407

IS - 1

ER -