High Intratumoral Stromal Content Defines Reactive Breast Cancer as a Low-risk Breast Cancer Subtype

Abstract

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 data sets (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 epidermal growth factor 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 sub-classify ER-positive/HER2-negative breast cancers.

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

“…Cluster 5 (reactive) had high levels of MYH11, HSP70, FIBRONECTIN, COLLAGEN VI, CAVEOLIN1 and RICTOR, as well as remarkably low levels of the proapoptotic mediator BAK , perhaps contributing to the cluster’s poor outcomes. Reactive cancer subtypes showed high levels of proteins that are likely produced in the tumor microenvironment as the result of interactions between cancer cells and cells in the microenvironment, including fibroblasts, as discussed previously for reactive breast cancer subtypes (Cancer Genome Atlas Network, 2012; Dennison et al, 2016). …”

Proteomic Features of Colorectal Cancer Identify Tumor Subtypes Independent of Oncogenic Mutations and Independently Predict Relapse-Free Survival

“…In the TCGA study however, Collagen VI is well represented in Cluster_V notable for a reactive/EMT signature and better relapse-free survival when compared to other clusters [7]. Additionally, Dennison et al recently identified a similarly reactive subtype of breast cancer by RPPA notable for high stromal content similarly associated with favorable outcomes [11]. Our findings are concordant with improved outcomes in high Collagen VI CRC expression [HR= 0.31 (95% CI 0.15, 0.65; p= 0.002)].…”

ColXα1 is a stromal component that colocalizes with elastin in the breast tumor extracellular matrix

“…However, these portend an adverse prognosis in triple negative tumors [11]. Dennison et al recently discovered that a particular stromal protein signature in breast carcinoma is associated with a highly differentiated phenotype [50]. The outcome analysis in our study identified significant correlation between ColXα1/elastin expression in the neoadjuvant-treated tumor but not in the adjuvant setting.…”