Format

Send to

Choose Destination
J Clin Invest. 2018 Dec 3;128(12):5235-5250. doi: 10.1172/JCI99974. Epub 2018 Oct 22.

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

Author information

1
Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2
Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
3
Department of Chemical Engineering, Tsinghua University, Beijing, China.
4
Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
5
Pathology Center, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
6
Department of Gastroenterology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
7
Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
8
Department of Breast Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
9
School of Medicine, Anhui University of Science & Technology, Huainan, Anhui, China.

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.

KEYWORDS:

Breast cancer; Cell Biology; Chemokines; Oncology

PMID:
30204129
PMCID:
PMC6264654
DOI:
10.1172/JCI99974
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center