Cold-inducible RNA-binding protein as a context-specific functional mediator of breast cancer metastasis.

Abstract

3136 Background: Cold-inducible RNA-binding protein (CIRBP) is a stress-induced mRNA-binding protein associated with clinical outcomes in a variety of human disease states. CIRBP’s role as a prognostic biomarker in breast cancer (BC) has yet to be established. Methods: We describe a clinically annotated tissue micro-array cohort of 1406 hormone receptor positive (HR+) and 281 triple negative primary breast cancers (TNBC) stained by immunohistochemistry (IHC) for CIRBP. Statistical analyses were performed with the Kaplan-Meier estimator, as well as univariate and multivariate Cox proportional-hazards models. Multivariate models incorporated tumor size, lymph node status, grade and CIRBP expression levels. Co-primary endpoints were overall survival (OS) and progression-free survival (PFS). MDA-MB-231 TNBC cells and MDA-MB-361 HR+ cells were used for CIRBP knockout (KO) by CRISPR/Cas9, and subsequent mammary fat pad injections were performed in immunocompromised mice. Results: In N=281 primary TNBCs, high levels of CIRBP expression by IHC was associated with poor prognosis in multivariate analysis (OS: adjusted hazard ratio (aHR) 2.05, 95% confidence interval (CI) 1.24-3.41, P=0.005. PFS: aHR 2.46, 95% CI 1.33-4.57, P=0.004). However, in N=1406 HR+ primary BC, CIRBP expression was correlated with favorable prognosis (OS: aHR 0.927, 95% CI 0.88-0.98, P=0.05. PFS: aHR 0.904, 95% CI 0.85-0.96, P=0.002). CIRBP KO had minimal impact on mammary fat pad primary tumor growth in both MDA-MB-231 and MDA-MB-361 cell models. However, CIRBP KO resulted in the inhibition of efficient spontaneous metastasis to the liver and lungs in TNBC MDA-MB-231 cells but not HR+ MDA-MB-361 cells. Conclusions: CIRBP expression is associated with poor prognosis in TNBC but not HR+ BC patients, a finding validated with CRISPR/Cas9 KO in representative model systems. This finding highlights the prognostic significance of CIRBP in TNBC and suggests differential underlying mRNA targets bound and modulated by CIRBP in TNBC and HR+ BC, respectively.