The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence

Jansson, Sara; Aaltonen, Kristina; Bendahl, Pär Ola; Falck, Anna Karin; Karlsson, Maria; Pietras, Kristian; Rydén, Lisa

doi:10.1007/s10549-018-4664-7

Cited by 70 publications

(56 citation statements)

References 31 publications

(41 reference statements)

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“…EGFR is a hall-mark of basal like breast cancer and has repeatedly been presented as a key player promoting EMT [49,50]. Interestingly, PDGFC is also associated with features of inferior prognosis in human breast cancer [27] and the PDGFC gene strongly correlates with gene-sets defining the EMT pathways supporting an association also for PDGFC with EMT [51]. The functional role of PDGFC in the EMT promoting process is, however, not settled.…”

Section: Discussionmentioning

confidence: 99%

“…The study was approved by the Lund University ethics committee (LU699-09, LU75-02), and all patients included provided written informed consent. Results of the observational study and information about the patient cohort have been described, including biomarker protocols and assessment, in detail previously [25][26][27]. Patients diagnosed with lobular carcinomas were excluded in the present study, as several studies have demonstrated a different expression pattern of E-cadherin in this type of breast cancer [28][29][30].…”

Section: Patientsmentioning

confidence: 99%

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Expression of epithelial-mesenchymal transition-related markers and phenotypes during breast cancer progression

Jørgensen

Forsare

Bendahl

et al. 2020

Breast Cancer Res Treat

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Purpose The study aimed to investigate expression of epithelial-to-mesenchymal transition (EMT)-related proteins and phenotypes during breast cancer progression and to relate this to patient outcome. Methods Protein expression patterns of E-cadherin, N-cadherin, twist, and vimentin were examined by immunohistochemistry on formalin-fixed paraffin-embedded samples from primary tumors (PTs) (n = 419), synchronous lymph node metastases (LNMs) (n = 131) and recurrences (n = 34) from patients included in an observational prospective primary breast cancer study. Markers were evaluated individually and combined as defined EMT phenotypes (epithelial, mesenchymal, partial EMT, and negative). EMT profiles were compared between matched tumor progression stages, and related to clinicopathological data and distant recurrence-free interval (DRFi). Results N-cadherin-positivity, vimentin-positivity, mesenchymal and partial EMT phenotypes were associated with more aggressive tumor characteristics such as triple-negative subtype. Single EMT markers and phenotype discordance rates between paired tumor samples were observed in the range of 2-35%. Non-epithelial phenotypes were more frequently identified in recurrences compared to PTs, however, no skewness of expression or phenotype was detected between PTs and matched LNMs or between PTs and matched recurrences (Exact McNemar test). Interestingly, patients with a twist positive PT had shorter DRFi, compared to patients with a twist negative PT (hazard ratio (HR) 2.4, 95% confidence interval (CI) 1.2-5.1, P = 0.02). Essentially, the same effect was seen in multivariable analysis (HR 2.5, 95% CI 0.97-6.6, P = 0.06). Conclusion The epithelial phenotype was indicated to be lost between PTs and recurrences as a reflection of tumor progression. Twist status of the PT was related to long-term prognosis warranting further investigation in larger cohorts.

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Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

Expression of epithelial-mesenchymal transition-related markers and phenotypes during breast cancer progression

Jørgensen

Forsare

Bendahl

et al. 2020

Breast Cancer Res Treat

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“…A recent study reporting immunohistochemical analyses of a cohort of 550 human breast cancer samples including 30 TNBCs reported expression of PDGFRβ in the stroma and not in tumor cells 56 , and suggested that the paracrine crosstalk existing between basal-like mammary cancer cells, expressing the PDGF-CC ligand, and cancer-associated fibroblasts, expressing both PDGFRβ and the cognate PDGFRα 57 , could be the most prominent route of PDGFR-dependent signal transduction in breast cancer. Herein, by extending the analysis on a TMA comprising 200 cases of human TNBC, we present novel data showing that PDGFRβ is also expressed in tumor cells belonging to a restricted subgroup of tumors of the mesenchymal subtype expressing either MMP-9 or ALDH proteins that appears as a highly invasive and stem-like phenotype.…”

Section: Discussionmentioning

confidence: 99%

Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRβ aptamer

Camorani¹,

Hill²,

Collina³

et al. 2018

Theranostics

102

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While the overall mortality for breast cancer has recently declined, management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and the lack of targeted therapies. Genomic profiling studies highlighted the high level of heterogeneity of this cancer, which comprises different subtypes with unique phenotypes and response to treatment. Platelet-derived growth factor receptor β (PDGFRβ) is an established mesenchymal/stem cell-specific marker in human glioblastoma and, as recently suggested, it may uniquely mark breast cancer cells with stem-like characteristics and/or that have undergone epithelial-mesenchymal transition.Methods: Immunohistochemical analysis for PDGFRβ expression was performed on a human TNBC tissue microarray. Functional assays were conducted on mesenchymal-like TNBC cells to investigate the effect of a previously validated PDGFRβ aptamer on invasive cell growth in three-dimensional culture conditions, migration, invasion and tube formation. The aptamer was labeled with a near-infrared (NIR) dye and its binding specificity to PDGFRβ was assessed both in vitro (confocal microscopy and flow cytometry analyses) and in vivo (fluorescence molecular tomography in mice bearing TNBC xenografts). A mouse model of TNBC lung metastases formation was established and NIR-labeled PDGFRβ aptamer was used to detect lung metastases in mice untreated or intravenously injected with unlabeled aptamer.Results: Here, we present novel data showing that tumor cell expression of PDGFRβ identifies a subgroup of mesenchymal tumors with invasive and stem-like phenotype, and propose a previously unappreciated role for PDGFRβ in driving TNBC cell invasiveness and metastases formation. We show that the PDGFRβ aptamer blocked invasive growth and migration/invasion of mesenchymal TNBC cell lines and prevented TNBC lung metastases formation. Further, upon NIR-labeling, the aptamer specifically bound to TNBC xenografts and detected lung metastases.Conclusions: We propose PDGFRβ as a reliable biomarker of a subgroup of mesenchymal TNBCs with invasive and stem-like phenotype as well as the use of the PDGFRβ aptamer as a high efficacious tool for imaging and suppression of TNBC lung metastases. This study will allow for the significant expansion of the current repertoire of strategies for managing patients with more aggressive TNBC.

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“…Moreover, in the current study, PDGFRB was demonstrated as an additional FA gene associated with GPER. Although the role of the PDGFB/PDGFRB axis in BC progression is still a subject of debate, PDGFRB overexpression was correlated with the acquisition of vascular-like functional properties of TNBC, suggesting its involvement in tumor aggressiveness [77,78]. From our correlation and pathway analysis, two members of the ECM-receptor interaction and the FA pathway, named PGF and VWF, which were indicated as prognostic markers in BC [79,80], appeared to be associated with GPER.…”

Section: Discussionmentioning

confidence: 73%

The G Protein-Coupled Estrogen Receptor (GPER) Expression Correlates with Pro-Metastatic Pathways in ER-Negative Breast Cancer: A Bioinformatics Analysis

Talia

Francesco

Rigiracciolo

et al. 2020

Cells

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The G protein-coupled estrogen receptor (GPER, formerly known as GPR30) is a seven-transmembrane receptor that mediates estrogen signals in both normal and malignant cells. In particular, GPER has been involved in the activation of diverse signaling pathways toward transcriptional and biological responses that characterize the progression of breast cancer (BC). In this context, a correlation between GPER expression and worse clinical-pathological features of BC has been suggested, although controversial data have also been reported. In order to better assess the biological significance of GPER in the aggressive estrogen receptor (ER)-negative BC, we performed a bioinformatics analysis using the information provided by The Invasive Breast Cancer Cohort of The Cancer Genome Atlas (TCGA) project and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets. Gene expression correlation and the statistical analysis were carried out with R studio base functions and the tidyverse package. Pathway enrichment analysis was evaluated with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway on the Database for Annotation, Visualization and Integrated Discovery (DAVID) website, whereas gene set enrichment analysis (GSEA) was performed with the R package phenoTest. The survival analysis was determined with the R package survivALL. Analyzing the expression data of more than 2500 primary BC, we ascertained that GPER levels are associated with pro-migratory and metastatic genes belonging to cell adhesion molecules (CAMs), extracellular matrix (ECM)-receptor interaction, and focal adhesion (FA) signaling pathways. Thereafter, evaluating the disease-free interval (DFI) in ER-negative BC patients, we found that the subjects expressing high GPER levels exhibited a shorter DFI in respect to those exhibiting low GPER levels. Overall, our results may pave the way to further dissect the network triggered by GPER in the breast malignancies lacking ER toward a better assessment of its prognostic significance and the action elicited in mediating the aggressive features of the aforementioned BC subtype.

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The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence

Cited by 70 publications

References 31 publications

Expression of epithelial-mesenchymal transition-related markers and phenotypes during breast cancer progression

Expression of epithelial-mesenchymal transition-related markers and phenotypes during breast cancer progression

Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRβ aptamer

The G Protein-Coupled Estrogen Receptor (GPER) Expression Correlates with Pro-Metastatic Pathways in ER-Negative Breast Cancer: A Bioinformatics Analysis

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