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 December 3, 2018; First 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 1

HIC1 deletion induces hyperplasia of mammary gland in vivo.

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HIC1 deletion induces hyperplasia of mammary gland in vivo. (A) Represen...
(A) Representative whole-mount staining of the fourth inguinal mammary glands at the indicated ages (4 months and 8 months) were prepared from Hic1+/+ mice or Hic1–/– mice and stained with carmine aluminum (n = 6 for each group). M, months. (B) H&E staining of the mammary glands of 6-month-old mice. (C) Immunofluorescence staining of luminal epithelial marker (K8) and myoepithelial markers (α-SMA) in the mammary glands of 6-month-old, 8-month-old, and 12-month-old mice. (D) Immunohistochemical staining of Ki67 and cyclin D1 in mammary glands of 6-month-old mice. The dot plots show the mean value for each immunoreactivity score (IRS) with statistical evaluation. Data are shown as mean ± SEM. n = 6. *P < 0.05, 2-tailed Student’s t test. (E) Box plots of HIC1 mRNA levels in paired normal breast/BrCa tissues (left, paired t tests), non-TNBC/TNBC tissues (middle, 2-tailed Student’s t tests), and BrCa tissues at different stages (right, 1-way ANOVA followed by Bonferroni’s post hoc test). Data were obtained from the TCGA data set (TCGA_BRCA_exp_HiSeqV2-2015-02-24). *P < 0.05; **P < 0.01; ***P < 0.001. (F) Kaplan-Meier plots of the relapse-free survival of patients with BrCa in whole data sets stratified by HIC1 expression. Data were acquired from the Kaplan-Meier plotter database. P = 0.00027, log-rank test (28). Representative images in this figure were obtained from at least 3 animals of each genotype.