Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Cell biology Oncology Article has an altmetric score of 4

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

  • Text
  • PDF
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

×

Figure 4

CXCL14 derived from HIC1-deleted BrCa cells mediates the activation of mammary fibroblasts.

Options: View larger image (or click on image) Download as PowerPoint
CXCL14 derived from HIC1-deleted BrCa cells mediates the activation of m...
(A) Left: NAF2 or NAF6 cells were treated with rhCXCL14 at various concentrations (0–200 ng/ml) for 4 days. The corresponding primary CAF2 or CAF6 cells were used as positive controls. Right: immortalized NAF10 cells stably overexpressed CXCL14. Cell lysates were analyzed by Western blot with antibodies against α-SMA, FAP, PDGFRα, and GAPDH. (B) Representative immunofluorescence staining detection of α-SMA, FAP, and PDGFRα expression in NAF6 or CAF6 cells treated similarly to the cells described in A. (C) NAF6 cells were cocultured with MCF7CtrlMCF7sgHIC1 or with T47DCtrlT47DsgHIC1 luminal BrCa cells for 4 days in the presence or absence of α-CXCL14 at 1 μg/ml or an isotype-matched IgG control. Cell lysates from NAF6 cells were analyzed by Western blot with antibodies against α-SMA, FAP, PDGFRα, and GAPDH. (D) Three MCF7 cell lines (Ctrl-NC, sgHIC1-NC, sgHIC1-shCXCL14) were injected bilaterally into the fourth mammary fat pads of female BALB/c nude mice (n = 10 per group). Tumor volumes were measured with calipers at the indicated time points. Data are shown as mean ± SD. ***P < 0.001, RM ANOVA followed by post hoc LSD test. (E) Photographs and weights of the tumors obtained from the animals described in D. Data are shown as mean ± SD. ***P < 0.001, 1-way ANOVA followed by Bonferroni’s post hoc test. (F) Representative immunohistochemical staining for Ki67 and stromal α-SMA in tumor tissues obtained from each experimental group. Dot plots show the mean value for the percentage of Ki67 or stromal α-SMA–positive cells with statistical evaluation (n = 5–6). 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.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Posted by 7 X users
54 readers on Mendeley
See more details