Characterization of type III TGF‐β receptor expression in invasive breast carcinomas: a potential new marker and target for triple negative breast cancer

Abstract

Invasive breast carcinomas are heterogeneous and exhibit distinct molecular features and biological behavior. Understanding the underlying molecular events that promote breast cancer progression is necessary to improve treatment and prognostication. TGF-β receptor III (TBR3) is a member of the TGF-β signaling pathway, with functions in cell proliferation and migration in malignancies, including breast cancer. Recent studies propose that TBR3 may function as a tumor suppressor and that its loss may correlate with disease progression. However, there are limited data on the expression of TBR3 in breast cancer in relationship to tumor type, hormonal receptor status and HER-2/neu, and patient outcome. In this study, we investigated the expression of TBR3 in a cohort of 205 primary invasive breast carcinomas in tissue microarrays (TMAs), with comprehensive clinical, pathological and follow-up information. Sections were stained for TBR3 and evaluated for intensity of reactivity based on a 4-tiered scoring system (1 to 4; TBR3 low=scores 1-2; TBR3 high=scores 3-4). Of the 205 invasive carcinomas, 123 were luminal type (95 type A, 28 type B), 8 were HER-2 type, and 62 were triple negative (TN). TBR3 was high in 112 (55 %) and low in 93 (45 %) cases. Low TBR3 was associated with higher histological grade and worse disease free and overall survival, all features of biologically aggressive breast carcinomas. TBR3 was significantly associated with the subtype of breast cancer, as low TBR3 was detected in 95 % of TN compared to 22 % of luminal tumors ( p<0.0001). We discovered a significant association between low TBR3 protein expression, TN breast cancer phenotype, and disease progression. These data suggest that TBR3 loss might be linked to the development of TN breast cancers and pave the way to investigating whether restoring TBR3 function may be a therapeutic strategy against TN breast carcinomas.

An interesting perspective on a well-studied pathway: does type III TGF-Β receptor have therapeutic potential?

“…The finding highlighted by the work of Pang et al (2014) supports and extends work done at the RNA level showing that lower expression of the type III TGF-β receptor (TBR3), or β-glycan predicts a poor outcome and increased invasiveness of breast cancer. TBR3 acts as a co-receptor for TGFβ isoforms.…”

Elucidation of Altered Pathways in Tumor-Initiating Cells of Triple-Negative Breast Cancer: A Useful Cell Model System for Drug Screening

“…Due to the complexity of TGF‐β signaling, the effect of the aberrant signaling in this cell line model is difficult to fully elucidate. Lower expression of TGFBR3, as detected in the tumor‐initiating H6 cells versus nontumorigenic G4 cells, has been correlated with worse disease‐free and overall survival in TNBC . TGFBR3 is reported as an important suppressor of breast cancer progression, which can attenuate TGF‐β signaling by binding to TGF‐β ligand followed by shedding of its extracellular domain, thereby preventing ligand to mediate intracellular signaling through TGFBR1 and TGFBR2 .…”