HIC1 deletion promotes breast cancer progression by activating tumor cell/fibroblast crosstalk
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
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
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Research Article Cell biology Oncology

HIC1 deletion promotes breast cancer progression by activating tumor cell/fibroblast crosstalk

Abstract

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 hypermethylated in cancer 1 (HIC1) in the mouse mammary gland might contribute to premalignant transformation in the early stage of tumor formation. Moreover, the chemokine (C-X-C motif) ligand 14 (CXCL14) secreted by HIC1-deleted BrCa cells bound to its 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 epithelial-mesenchymal transition (EMT) by the C-C chemokine ligand 17 (CCL17)/CC chemokine receptor 4 (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. Exploring the progression of BrCa from the perspective of microenvironment will be beneficial for identifying the potential prognostic markers of breast tumor and providing more effective treatment strategies.

Authors

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

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Figure 2

HIC1-deleted BrCa cells induce the activation of stromal fibroblasts in mammary gland.

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HIC1-deleted BrCa cells induce the activation of stromal fibroblasts in ...
(A) Representative 3 immunohistochemistry images for α-SMA in mammary glands of 6-month-old mice. Positive staining in the mammary gland stroma of Hic1–/– mice is indicated by red arrows (n = 3 for each group). (B) CRISPR-Cas9–mediated HIC1 deletion in MCF7 and T47D luminal BrCa cells. Cell lysates were analyzed by Western blot with antibodies against HIC1 and GAPDH. sg3 and sg4 represent 2 different interference sgRNA sequences. Ctrl, control. (C) Representative primary NAFs and CAFs isolated from human BrCa tissues. Western blot analysis of cell lysates was performed using antibodies against α-SMA, FAP, PDGFRα, and GAPDH. (D) Schematic showing primary NAFs cocultured with MCF7CtrlMCF7sgHIC1 or T47DCtrlT47DsgHIC1 luminal BrCa cells in a Transwell apparatus (0.4 μm pore size) for 4 days. (E) Western blot analysis of lysates of NAF6 cells that were cocultured with MCF7CtrlMCF7sgHIC1 or T47DCtrlT47DsgHIC1 luminal BrCa cells for 4 days. Antibodies against α-SMA, FAP, PDGFRα, and GAPDH were used. (F) Immunofluorescence staining for the detection of α-SMA expression in NAF6 cells that were cocultured with MCF7CtrlMCF7sgHIC1 or T47DCtrlT47DsgHIC1 luminal BrCa cells for 4 days.