Abstract
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.
Highlights
Human epidermal growth factor receptor 2 (HER2)-driven breast cancer is correlated with poor prognosis, especially during its later stages
Integrin α3β1 is not needed for the onset of HER2-driven mammary tumorigenesis To investigate the role of integrin α3β1 in HER2-mediated mammary tumorigenesis and tumor progression in vivo, we employed the widely used breast cancer mouse model, MMTV-cNeu, designed to promote development of mammary tumors as a result of overexpression of HER2/ Neu oncogene under the transcriptional control of the mouse mammary tumor virus (MMTV) promoter [2]
Histological analysis of the tumors revealed that mice developed two types of mammary adenocarcinomas, i.e., solid and cystic/ hemorrhagic tumors (Additional file 1: Figure S1a), which were represented in both groups (Additional file 1: Figure S1b)
Summary
HER2-driven breast cancer is correlated with poor prognosis, especially during its later stages. It has become clear that the function of integrins within both tumor cells and tumor environment is highly complex, which is reflected by the fact that they often play opposing roles in the initiation and progression of different tumor types [10]. This is especially prominent for integrin α3β1, a laminin-332- and laminin-511-binding integrin that is expressed mostly in the epithelia of the kidneys, lungs, intestine, skin, bladder, and stomach. This illustrates that there is a need to investigate its clinical significance in relation to the phenotypical and histological variants of specific types of tumors
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