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Absence of integrin ?3?1 promotes the progression of HER2-driven breast cancer in vivo.

ABSTRACT:

Background

HER2-driven breast cancer is correlated with poor prognosis, especially during its later stages. Numerous studies have shown the importance of the integrin ?3?1 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 ?3?1 in a genetically engineered mouse model of HER2-driven mammary tumorigenesis.

Methods

To investigate the role of ?3?1 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 ?3?1 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 ?3?1 in initial adhesion to laminin and collagen was assessed using adhesion assays and immunofluorescence.

Results

Tumor onset in mice was independent of the presence of ?3?1. In contrast, the depletion of ?3?1 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 ?3?1 in HER2-driven cells depended on the composition of the extracellular matrix and the interstitial fluid flow.

Conclusion

Downregulation of ?3?1 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 ?3?1 was not observed in triple-negative mammary carcinoma cells, illustrating the tumor type-specific and complex function of ?3?1 in breast cancer.

SUBMITTER: Ramovs V

PROVIDER: S-EPMC6525362 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

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

Ramovs Veronika V Secades Pablo P Song Ji-Ying JY Thijssen Bram B Kreft Maaike M Sonnenberg Arnoud A

Breast cancer research : BCR 20190517 1

<h4>Background</h4>HER2-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.<h4> ...[more]

PMID: 31101121

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