Absence of integrin α3β1 promotes the progression of HER2-driven breast cancer in vivo

Breast Cancer Research

Ji-Ying Song¹  Maaike Kreft²  Pablo Secades²  Arnoud Sonnenberg²  Veronika Ramovs²  Bram Thijssen³ 

[1] grid.430814.a, Department of Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;grid.430814.a, Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands;grid.430814.a, Oncode Institute and Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands;

关键词: Integrin α3β1;    HER2;    MMTV-cNeu;    Metastasis;    Breast cancer;    Extracellular matrix;    Collagen;    Adhesion;    Interstitial fluid flow;   

DOI  :  10.1186/s13058-019-1146-8

来源: publisher

【 摘 要 】

BackgroundHER2-driven breast cancer is correlated with poor prognosis, especially during its later stages. Numerous studies have shown the importance of the integrin α3β1 during the initiation and progression of breast cancer; however, its role in this disease is complex and often opposite during different stages and in different types of tumors. In this study, we aim to elucidate the role of integrin α3β1 in a genetically engineered mouse model of HER2-driven mammary tumorigenesis.MethodsTo investigate the role of α3β1 in HER2-driven tumorigenesis in vivo, we generated a HER2-driven MMTV-cNeu mouse model of mammary tumorigenesis with targeted deletion of Itga3 (Itga3 KO mice). We have further used several established triple-negative and HER2-overexpressing human mammary carcinoma cell lines and generated ITGA3-knockout cells to investigate the role of α3β1 in vitro. Invasion of cells was assessed using Matrigel- and Matrigel/collagen I-coated Transwell assays under static or interstitial fluid flow conditions. The role of α3β1 in initial adhesion to laminin and collagen was assessed using adhesion assays and immunofluorescence.ResultsTumor onset in mice was independent of the presence of α3β1. In contrast, the depletion of α3β1 reduced the survival of mice and increased tumor growth and vascularization. Furthermore, Itga3 KO mice were significantly more likely to develop lung metastases and had an increased metastatic burden compared to WT mice. In vitro, the deletion of ITGA3 caused a significant increase in the cellular invasion of HER2-overexpressing SKBR3, AU565, and BT474 cells, but not of triple-negative MDA-MB-231. This invasion suppressing function of α3β1 in HER2-driven cells depended on the composition of the extracellular matrix and the interstitial fluid flow.ConclusionDownregulation of α3β1 in a HER2-driven mouse model and in HER2-overexpressing human mammary carcinoma cells promotes progression and invasiveness of tumors. The invasion-suppressive role of α3β1 was not observed in triple-negative mammary carcinoma cells, illustrating the tumor type-specific and complex function of α3β1 in breast cancer.

【 授权许可】

CC BY