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 7

CCL17 secreted by CAFs promotes lung metastasis of BrCa xenografts.

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CCL17 secreted by CAFs promotes lung metastasis of BrCa xenografts. (A) ...
(A) Schematic showing the lung metastasis model of BrCa xenografts. MDA-231-LM2 BrCa cells mixed with primary NAF8 or CAF8 cells at a ratio of 3:1 were implanted bilaterally into the mammary fat pads of BALB/c nude mice (n = 12 per group). When the xenografts became palpable 2 weeks later, control IgG or αCCL17 (1 μg/mouse) was then injected via the tail vein every 3 days for 30 days; the mice were then euthanized. (B) Representative bioluminescence imaging of the harvested lungs (left) and quantification of their bioluminescent signals (right, n = 6). Data are shown as mean ± SD. *P < 0.05, 1-way ANOVA followed by Bonferroni’s post hoc test. (C) Representative immunohistochemical staining for human cytokeratin of each group’s lung tissues and for N-cadherin and vimentin in orthotopic xenografts. Dot plots show the mean values for the percentage of human cytokeratin-, N-cadherin–, or vimentin-positive cells with statistical evaluation (n = 5). Data are shown as mean ± SEM. n = 3 independent experiments. **P < 0.01; ***P < 0.001, 1-way ANOVA followed by Bonferroni’s post hoc test. (D) Kaplan-Meier survival curves of BALB/c nude mice that received the indicated treatments. *P < 0.05, log-rank test. (E) Kaplan-Meier plots of distant metastasis-free survival of systemically untreated patients (n = 543) stratified by CCL17 expression. Data were obtained from the Kaplan-Meier plotter database. P = 0.04, log-rank test (28).