Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

BACKGROUND: A better definition of biomarkers and biological processes related to local recurrence and disease progression is highly warranted for ductal breast carcinoma in situ (DCIS). Stromal-epithelial interactions are likely of major importance for the biological, clinical, and pathological distinctions between high- and low-risk DCIS cases.

METHODS: Stromal platelet derived growth factor receptor (PDGFR) was immunohistochemically assessed in two DCIS patient cohorts (n = 458 and n = 80). Cox proportional hazards models were used to calculate the hazard ratios of recurrence. The molecular mechanisms regulating stromal PDGFR expression were investigated in experimental in vitro co-culture systems of DCIS cells and fibroblasts and analyzed using immunoblot and quantitative real-time PCR. Knock-out of JAG1 in DCIS cells and NOTCH2 in fibroblasts was obtained through CRISPR/Cas9. Experimental data were validated by mammary fat pad injection of DCIS and DCIS-JAG1 knock-out cells (10 mice per group). All statistical tests were two-sided.

RESULTS: PDGFRα(low)/PDGFRβ(high) fibroblasts were associated with increased risk for recurrence in DCIS (univariate hazard ratio = 1.59, 95% confidence interval [CI] = 1.02 to 2.46; P = .04 Wald test; multivariable hazard ratio = 1.78, 95% CI = 1.07 to 2.97; P = .03). Tissue culture and mouse model studies indicated that this fibroblast phenotype is induced by DCIS cells in a cell contact-dependent manner. Epithelial Jagged1 and fibroblast Notch2 were identified through loss-of-function studies as key juxtacrine signaling components driving the formation of the poor prognosis-associated fibroblast phenotype.

CONCLUSIONS: A PDGFRα(low)/PDGFRβ(high) fibroblast subset was identified as a marker for high-risk DCIS. The Jagged-1/Notch2/PDGFR stroma-epithelial pathway was described as a novel signaling mechanism regulating this poor prognosis-associated fibroblast subset. In general terms, the study highlights epithelial-stromal crosstalk in DCIS and contributes to ongoing efforts to define clinically relevant fibroblast subsets and their etiology.

Detaljer

Författare
  • Carina Strell
  • Janna Paulsson
  • Shao-Bo Jin
  • Nicholas P Tobin
  • Artur Mezheyeuski
  • Pernilla Roswall
  • Ceren Mutgan
  • Nicholas Mitsios
  • Hemming Johansson
  • Sarah Marie Wickberg
  • Jessica Svedlund
  • Mats Nilsson
  • Per Hall
  • Jan Mulder
  • Derek C Radisky
  • Kristian Pietras
  • Jonas Bergh
  • Urban Lendahl
  • Fredrik Wärnberg
  • Arne Östman
Enheter & grupper
Externa organisationer
  • Lund University
  • Uppsala universitet
  • Mayo Clinic Florida
  • Stockholms universitet
  • Karolinska Institute
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
  • Cell- och molekylärbiologi
Originalspråkengelska
Sidor (från-till)983-995
TidskriftJournal of the National Cancer Institute
Volym111
Utgåva nummer9
Tidigt onlinedatum2019 feb 28
StatusPublished - 2019
PublikationskategoriForskning
Peer review utfördJa

Bibliografisk information

© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.