HIC1 deletion promotes breast cancer progression by activating tumor cell/fibroblast crosstalk
Yingying Wang, … , Jinsong Lu, Jianhua Wang
Yingying Wang, … , Jinsong Lu, Jianhua Wang
Published September 11, 2018
Citation Information: J Clin Invest. 2018;128(12):5235-5250. https://doi.org/10.1172/JCI99974.
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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 8

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

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HIC1-CXCL14-CCL17 loop is associated with malignant progression in BrCa ...
(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.