uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ
Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Solna, Sweden.
Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden.
Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.
Karolinska Inst, Dept Oncol Pathol, CCK, Stockholm, Sweden.
Show others and affiliations
2019 (English)In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 111, no 9, p. 983-995, article id djy234Article in journal (Refereed) Published
Abstract [en]

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: PDGFR alpha((low))/PDGFR beta((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 PDGFR alpha((low))/PDGFR beta((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.

Place, publisher, year, edition, pages
2019. Vol. 111, no 9, p. 983-995, article id djy234
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-397124DOI: 10.1093/jnci/djy234ISI: 000493067400014PubMedID: 30816935OAI: oai:DiVA.org:uu-397124DiVA, id: diva2:1374252
Funder
Swedish Cancer Society, 150895Swedish Research Council, Diarienr 349-2006-160The Cancer Research Funds of RadiumhemmetAvailable from: 2019-11-29 Created: 2019-11-29 Last updated: 2019-11-29Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Mezheyeuski, ArturNilsson, MatsWärnberg, Fredrik

Search in DiVA

By author/editor
Mezheyeuski, ArturNilsson, MatsWärnberg, Fredrik
By organisation
Experimental and Clinical OncologyScience for Life Laboratory, SciLifeLabMolecular toolsEndocrine Surgery
In the same journal
Journal of the National Cancer Institute
Cancer and OncologyCell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 3 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf