Breast cancer (BrCa) is the malignant tumor that most seriously threatens female health; however, the molecular mechanism underlying its progression remains unclear. Here, we found that conditional deletion of HIC1 in the mouse mammary gland might contribute to premalignant transformation in the early stage of tumor formation. Moreover, the chemokine CXCL14 secreted by HIC1-deleted BrCa cells bound to its novel cognate receptor GPR85 on mammary fibroblasts in the microenvironment and was responsible for activating these fibroblasts via the ERK1/2, Akt, and neddylation pathways, whereas the activated fibroblasts promoted BrCa progression via the induction of the epithelial–mesenchymal transition (EMT) by the CCL17/CCR4 axis. Finally, we confirmed that the HIC1-CXCL14-CCL17 loop was associated with the malignant progression of BrCa. Therefore, the crosstalk between HIC1-deleted BrCa cells and mammary fibroblasts might play a critical role in BrCa development. Taken together, exploring the progression of BrCa from the perspective of microenvironment will be beneficial for identifying the potential prognostic marker of breast tumor and providing the more effective treatment strategy.
Yingying Wang, Xiaoling Weng, Luoyang Wang, Mingang Hao, Yue Li, Lidan Hou, Yu Liang, Tianqi Wu, Mengfei Yao, Guowen Lin, Yiwei Jiang, Guohui Fu, Zhaoyuan Hou, Xiangjun Meng, Jinsong Lu, Jianhua Wang