TY - JOUR
T1 - High intratumoral stromal content defines reactive breast cancer as a low-risk breast cancer subtype
AU - Dennison, Jennifer B.
AU - Shahmoradgoli, Maria
AU - Liu, Wenbin
AU - Ju, Zhenlin
AU - Meric-Bernstam, Funda
AU - Perou, Charles M.
AU - Sahin, Aysegul A.
AU - Welm, Alana
AU - Oesterreich, Steffi
AU - Sikora, Matthew J.
AU - Brown, Robert E.
AU - Mills, Gordon B.
N1 - Funding Information:
F. Meric-Bernstam reports receiving commercial research grants from Aileron, AstraZeneca, Bayer, Calithera, Debiopharma, Genentech, Novartis, and Taiho and is a consultant/advisory board member for Celgene, Genentech, Inflection Biosciences, Novartis, and Roche. C.M. Perou is an employee of, has ownership interest in (including patents), and is a consult/advisory board member for Bioclassifier LLC. G.B. Mills reports receiving commercial research grants from Adelson Medical Research Foundation, AstraZeneca, Clinical Outcome Technologies, Illumina, Karus, Nanostring, and Takeda/Millennium Pharmaceuticals; speakers bureau honoraria from Allostery, AstraZeneca, Eli Lilly, ImmunoMet, ISIS Pharmaceuticals, Novartis, Nuevolution, and Symphogen; has ownership interests (including patents) in Catena Pharmaceuticals, ImmunoMet, Myriad Genetics, PTV Ventures, and Spindletop Ventures; and is a consultant/advisory board member for Adventist Health, Allostery, AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, Eli Lilly, ImmunoMet, ISIS Pharmaceuticals, MedImmune, Novartis, Precision Medicine, Provista Diagnostics, Signalchem Lifesciences, Symphogen, Takeda/Millennium Pharmaceuticals, Tarveda, and Tau Therapeutics. No potential conflicts of interest were disclosed by the other authors. The authors thank Pamela K. Johnston for help with the IHC assays and Jared Burks in the North Campus Flow Cytometry and Cellular Imaging Core Facility at MD Anderson. They also thank the work of many investigators in the generation of data for the TCGA cohort, specifically for this article, the TCGA Pathology Team including Andrew H. Beck, Yujing J. Heng, Susan C. Lester, Gary M.K. Tse, Rachel E. Factor, Laura C. Collins, Kimberly H. Allison, and Yunn-Yi Chen. This work was supported in part by the Susan G. Komen Foundation (KG081694); GlaxoSmithKline; American Cancer Society Clinical Research Professorship Grant (CRP-07-234); Entertainment Industry Foundation; Breast Cancer Research Foundation; and Susan G. Komen for the Cure Scientific Advisory Council Grant (SAC100013); and the NIH through MD Anderson Cancer Center Support Grant CA016672. J.B. Dennison was supported by a GlaxoSmithKline TRIUMPH post-doctoral fellowship and the American Cancer Society, Joe and Jessie Crump Medical Research Fund Postdoctoral Fellowship. Funding was also supported by the DoD Breast Cancer Research Program #W81XWH-12-1-0077 (A. Welm), BCRF (S. Oesterreich), and a DoD BCRP Postdoctoral Fellowship BC11061 and NIH K99 CA193734 (M.J. Sikora). C.M. Perou was supported by NCI Breast SPORE program (P50-CA58223-09A1) and R01-CA148761. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
PY - 2016/10/15
Y1 - 2016/10/15
N2 - Purpose: The current study evaluated associative effects of breast cancer cells with the tumor microenvironment and its influence on tumor behavior. Experimental Design: Formalin-fixed, paraffin-embedded tissue and matched protein lysates were evaluated from two independent breast cancer patient datasets (TCGA and MD Anderson). Reverse-phase protein arrays (RPPA) were utilized to create a proteomics signature to define breast tumor subtypes. Expression patterns of cell lines and normal breast tissues were utilized to determine markers that were differentially expressed in stroma and cancer cells. Protein localization and stromal contents were evaluated for matched cases by imaging. Results: A subtype of breast cancers designated "Reactive," previously identified by RPPA that was not predicted by mRNA profiling, was extensively characterized. These tumors were primarily estrogen receptor (ER)-positive/human EGF receptor (HER)2-negative, low-risk cancers as determined by enrichment of low-grade nuclei, lobular or tubular histopathology, and the luminal A subtype by PAM50. Reactive breast cancers contained high numbers of stromal cells and the highest extracellular matrix content typically without infiltration of immune cells. For ER-positive/HER2-negative cancers, the Reactive classification predicted favorable clinical outcomes in the TCGA cohort (HR, 0.36; P < 0.05). Conclusions: A protein stromal signature in breast cancers is associated with a highly differentiated phenotype. The stromal compartment content and proteins are an extended phenotype not predicted by mRNA expression that could be utilized to subclassify ER-positive/HER2-negative breast cancers.
AB - Purpose: The current study evaluated associative effects of breast cancer cells with the tumor microenvironment and its influence on tumor behavior. Experimental Design: Formalin-fixed, paraffin-embedded tissue and matched protein lysates were evaluated from two independent breast cancer patient datasets (TCGA and MD Anderson). Reverse-phase protein arrays (RPPA) were utilized to create a proteomics signature to define breast tumor subtypes. Expression patterns of cell lines and normal breast tissues were utilized to determine markers that were differentially expressed in stroma and cancer cells. Protein localization and stromal contents were evaluated for matched cases by imaging. Results: A subtype of breast cancers designated "Reactive," previously identified by RPPA that was not predicted by mRNA profiling, was extensively characterized. These tumors were primarily estrogen receptor (ER)-positive/human EGF receptor (HER)2-negative, low-risk cancers as determined by enrichment of low-grade nuclei, lobular or tubular histopathology, and the luminal A subtype by PAM50. Reactive breast cancers contained high numbers of stromal cells and the highest extracellular matrix content typically without infiltration of immune cells. For ER-positive/HER2-negative cancers, the Reactive classification predicted favorable clinical outcomes in the TCGA cohort (HR, 0.36; P < 0.05). Conclusions: A protein stromal signature in breast cancers is associated with a highly differentiated phenotype. The stromal compartment content and proteins are an extended phenotype not predicted by mRNA expression that could be utilized to subclassify ER-positive/HER2-negative breast cancers.
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U2 - 10.1158/1078-0432.CCR-16-0171
DO - 10.1158/1078-0432.CCR-16-0171
M3 - Article
C2 - 27172895
AN - SCOPUS:84991594403
VL - 22
SP - 5068
EP - 5078
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 20
ER -