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SHR Neuro Cancer Cardio Lipid Metab Microb

Strell, C; Paulsson, J; Jin, SB; Tobin, NP; Mezheyeuski, A; Roswall, P; Mutgan, C; Mitsios, N; Johansson, H; Wickberg, SM; Svedlund, J; Nilsson, M; Hall, P; Mulder, J; Radisky, DC; Pietras, K; Bergh, J; Lendahl, U; Wärnberg, F; Östman, A.
Impact of Epithelial-Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ.
J Natl Cancer Inst. 2019; 111(9):983-995 Doi: 10.1093/jnci/djy234 [OPEN ACCESS]
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Co-authors Med Uni Graz: Mutgan Redolfi Ayse Ceren
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Abstract:: 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. 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. 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. 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. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
Find related publications in this database (using NLM MeSH Indexing): Adult -; Aged -; Aged, 80 and over -; Animals -; Biomarkers, Tumor -; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Cancer-Associated Fibroblasts - metabolism; Carcinoma, Intraductal, Noninfiltrating - metabolism; Carcinoma, Intraductal, Noninfiltrating - mortality; Carcinoma, Intraductal, Noninfiltrating - pathology; Cell Communication -; Cell Line, Tumor -; Coculture Techniques -; Computational Biology - methods; Disease Models, Animal -; Epithelial Cells - metabolism; Female -; Gene Expression Profiling -; Humans -; Immunohistochemistry -; Mice -; Middle Aged -; Neoplasm Grading -; Prognosis -; Receptors, Platelet-Derived Growth Factor - genetics; Receptors, Platelet-Derived Growth Factor - metabolism; Stromal Cells - metabolism