Dataset Information

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

ABSTRACT:

Purpose

The platelet-derived growth factor (PDGF) signalling pathway is often dysregulated in cancer and PDGF-receptor expression has been linked to unfavourable prognostic factors in breast cancer (e.g. ER negativity, high Ki67 and high grade). This study aimed to evaluate the expression of PDGFR?, PDGFR? and ligand PDGF-CC in breast cancer in relation to molecular subtypes and prognosis.

Methods

Protein expression of tumour and/or stromal cell PDGFR?, PDGFR? and PDGF-CC was evaluated in primary tumours (N = 489), synchronous lymph node metastases (N = 135) and asynchronous recurrences (N = 39) using immunohistochemistry in a prospectively maintained cohort of primary breast cancer patients included during 1999-2003. Distant recurrence-free interval (DRFi) was the primary end-point.

Results

High expression of all investigated PDGF family members correlated to increasing Nottingham histopathological grade and high Ki67. Tumour cells displayed high expression of PDGFR? in 20%, and PDGF-CC in 21% of primary tumours, which correlated with the triple-negative subtype (TNBC). Patients with high PDGF-CC had inferior prognosis (P = 0.04) in terms of 5-year DRFi, whereas PDGFR? was up-regulated in lymph node metastasis and recurrences compared to primary tumours. High primary tumour PDGFR? was associated with increased risk of central nervous system (CNS) recurrence.

Conclusions

High PDGFR? and PDGF-CC expression were linked to breast cancer with an aggressive biological phenotype, e.g. the TNBC subtype, and high PDGF-CC increased the risk of 5-year distant recurrence. Tumour cell PDGFR? was significantly up-regulated in lymph node metastases and asynchronous recurrences. Our findings support an active role of the PDGF signalling pathway in tumour progression.

SUBMITTER: Jansson S

PROVIDER: S-EPMC5945746 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Jansson Sara S Aaltonen Kristina K Bendahl Pär-Ola PO Falck Anna-Karin AK Karlsson Maria M Pietras Kristian K Rydén Lisa L

Breast cancer research and treatment 20180129 2

<h4>Purpose</h4>The platelet-derived growth factor (PDGF) signalling pathway is often dysregulated in cancer and PDGF-receptor expression has been linked to unfavourable prognostic factors in breast cancer (e.g. ER negativity, high Ki67 and high grade). This study aimed to evaluate the expression of PDGFRα, PDGFRβ and ligand PDGF-CC in breast cancer in relation to molecular subtypes and prognosis.<h4>Methods</h4>Protein expression of tumour and/or stromal cell PDGFRα, PDGFRβ and PDGF-CC was eval ...[more]

PMID: 29380207

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Project description:BackgroundApproximately two thirds of patients with localized triple-negative breast cancer (TNBC) harbor residual disease (RD) after neoadjuvant chemotherapy (NAC) and have a high risk-of-recurrence. Targeted therapeutic development for TNBC is of primary significance as no targeted therapies are clinically indicated for this aggressive subset. In view of this, we conducted a comprehensive molecular analysis and correlated molecular features of chemorefractory RD tumors with recurrence for the purpose of guiding downstream therapeutic development.MethodsWe assembled DNA and RNA sequencing data from RD tumors as well as pre-operative biopsies, lymphocytic infiltrate, and survival data as part of a molecular correlative to a phase II post-neoadjuvant clinical trial. Matched somatic mutation, gene expression, and lymphocytic infiltrate were assessed before and after chemotherapy to understand how tumors evolve during chemotherapy. Kaplan-Meier survival analyses were conducted categorizing cancers with TP53 mutations by the degree of loss as well as by the copy number of a locus of 18q corresponding to the SMAD2, SMAD4, and SMAD7 genes.ResultsAnalysis of matched somatic genomes pre-/post-NAC revealed chaotic acquisition of copy gains and losses including amplification of prominent oncogenes. In contrast, significant gains in deleterious point mutations and insertion/deletions were not observed. No trends between clonal evolution and recurrence were identified. Gene expression data from paired biopsies revealed enrichment of actionable regulators of stem cell-like behavior and depletion of immune signaling, which was corroborated by total lymphocytic infiltrate, but was not associated with recurrence. Novel characterization of TP53 mutation revealed prognostically relevant subgroups, which were linked to MYC-driven transcriptional amplification. Finally, somatic gains in 18q were associated with poor prognosis, likely driven by putative upregulation of TGFß signaling through the signal transducer SMAD2.ConclusionsWe conclude TNBCs are dynamic during chemotherapy, demonstrating complex plasticity in subclonal diversity, stem-like qualities, and immune depletion, but somatic alterations of TP53/MYC and TGFß signaling in RD samples are prominent drivers of recurrence, representing high-yield targets for additional interrogation.

Dataset Information

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

Purpose

Methods

Results

Conclusions

Publications

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

Similar Datasets

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