Expression of the chemokine CXCL14 in the tumour stroma is an independent marker of survival in breast cancer

Abstract

Background:Expression of the chemokine CXCL14 has previously been shown to be elevated in the tumour stroma of, for example, prostate and breast cancer. Cancer-associated fibroblast-derived CXCL14 enhances tumour growth in mouse models of prostate and breast cancer. However, the prognostic significance of compartment-specific expression of CXCL14 has not been studied.Methods:CXCL14 mRNA expression was analysed in a breast cancer tissue microarray (TMA) of formalin-fixed, paraffin-embedded tumours by the RNAscope 2.0 Assay. Epithelial and stromal expression was analysed separately and correlated with clinicopathological characteristics and survival.Results:CXCL14 was variably and independently expressed in malignant and stromal cells of breast cancer. Total and stromal expression of CXCL14 did not associate with clinicopathological parameters. Epithelial CXCL14 expression was significantly associated with oestrogen receptor α (ERα)-positive tumours and lower proliferation status. Total CXCL14 expression correlated significantly with shorter breast cancer-specific and recurrence-free survival. High stromal, but not epithelial, CXCL14 expression was significantly associated with shorter survival in univariable and multivariable analyses. Moreover, the correlation between stromal CXCL14 expression and survival was more prominent in ER negative, triple negative and basal-like breast cancers.Conclusions:The identification of prognostic significance of stromal CXCL14 in breast cancer demonstrates novel clinical relevance of a stroma-derived secreted factor and illustrates the importance of tumour compartment-specific analyses. On the basis of the prognostic signals from difficult-to-treat subgroups, CXCL14 should also be considered as a candidate drug target.

A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer

“…Earlier studies have identified stromal, but not epithelial, CXCL14 as a bad prognosis marker in breast cancer (1). The correlative data of this study support the notion of functional clinical relevant interaction between CXCL14 and ACKR2.…”

“…This study develops recent correlative studies that have indicated clinical relevance, in breast cancer, of stroma-derived expression of the chemokine CXCL14 by demonstrating signifi-cant and independent associations between high stromal CXCL14 expression and shorter survival in a population-based breast cancer cohort. Notably, epithelial expression of CXCL14 did not have an impact on breast cancer outcome (1).…”

Cancer-associated fibroblast heterogeneity in axillary lymph nodes drives metastases in breast cancer through complementary mechanisms

“…Axillary metastatic LN exhibit four CAF subsets (CAF-S1 to S4) but are highly enriched in αSMA+ CAF-S1 and CAF-S4 subsets. The abundance of αSMA+ CAF at PT has been associated with poor prognosis in BC 17,[44][45][46][47][48] . In agreement with our findings, a recent study reported that the global stromal content in metastatic LN provides a prognostic stratification of BC patients 49 .…”

Identification of Potential Therapeutic Targets Among CXC Chemokines in Breast Tumor Microenvironment Using Integrative Bioinformatics Analysis

“…Epithelial CXCL14 levels are markedly correlated with ER + tumors and lower proliferation status. Interestingly, total (epithelial and stromal) CXCL14 level is dramatically associated with decreased RFS [60]. Cross-talk between cancer cells and cancer-associated fibroblasts (CAFs) is also relevant to cancer research.…”