Figure 8. HIC1-CXCL14-CCL17 loop is associated with malignant progression in BrCa patients.

(A) Percentages of low and high expression of epithelial HIC1 (upper), stromal CXCL14 (middle), and stromal CCL17 (bottom) in benign breast tissue and various BrCa subtypes are shown as a pie chart. P vs. benign, χ² test. (B) Representative IHC images showing the correlation between epithelial HIC1 expression and stromal CXCL14/CCL17 expression in 228 benign and malignant breast tumor samples. Broken lines indicate the margins of the tumor. (C) Schematic model showing how HIC1-mediated crosstalk between cancer cells and mammary fibroblasts promotes BrCa progression. Conditional deletion of HIC1 in the mouse mammary gland may contribute to premalignant transformation at the early stage of breast tumor formation. Moreover, chemokine CXCL14 secreted by HIC1-deleted BrCa cells binds to its cognate receptor GPR85 on mammary fibroblasts in the microenvironment, thereby activating the fibroblasts through the ERK1/2, Akt, and neddylation pathways. The activated fibroblasts in turn promote BrCa progression through induction of EMT by activation of the CCL17/CCR4 chemokine axis.