Abstract
BackgroundAlthough integrins have been implicated in the progression of breast cancer, the exact mechanism whereby they exert this regulation is clearly not understood. To understand the role of integrins in breast cancer, we examined the expression levels of several integrins in mouse breast cancer cell lines by flow cytometry and the data were validated by Western and RT-PCR analysis. The importance of integrins in cell migration and cell invasion was examined by in vitro assays. Further the effect of integrins on metastasis was investigated by in vivo experimental metastasis assays using mouse models.ResultsIntegrin α5 subunit is highly expressed in the nonmetastatic cell line 67NR and is significantly low in the highly invasive cell line 4T1. In contrast, expression levels of integrin α6 subunit are high in 4T1 cells and low in 67NR cells. In vitro data indicated that overexpression of α5 subunit and knockdown of α6 integrin subunit inhibited cell proliferation, migration, and invasion. Our in vivo findings indicated that overexpression of integrin α5 subunit and knockdown of α6 subunit decreased the pulmonary metastasis property of 4T1 cells. Our data also indicated that overexpression of alpha 5 integrin subunit and suppression of alpha6 integrin subunit inhibited cells entering into S phase by up-regulating p27, which results in downregulation of cyclinE/CDK2 complexes, This suggests that these integrins regulate cell growth through their effects on cell-cycle-regulated proteins. We also found that modulation of these integrins upregulates E2F, which may induce the expression of chk1 to regulate cdc25A/cyclin E/CDK2/Rb in a feedback loop mechanism.ConclusionThis study indicates that Integrin α5 subunit functions as a potential metastasis suppressor, while α6 subunit functions as a metastasis promoter. The modulation of integrins reduces cdc25 A, another possible mechanism for downregulation of CDK2. Taken together we demonstrate a link between integrins and the chk1-cdc25-cyclin E/CDK2-Rb pathway.
Highlights
Integrins have been implicated in the progression of breast cancer, the exact mechanism whereby they exert this regulation is clearly not understood
Our study shows that integrin a5 subunit functions as a candidate metastasis suppressor, while a6 subunit promotes tumor metastasis in 4T1 cell lines through the modulation of pathways regulated by the cell cycle
In 4T1 cells integrin a5 subunit levels are low and integrin a6 subunit levels are high Since integrins are thought to have a major role in regulating tumor growth and metastasis, we examined the expression levels of integrins in highly invasive
Summary
Integrins have been implicated in the progression of breast cancer, the exact mechanism whereby they exert this regulation is clearly not understood. Tumor metastasis is a highly complex multistep process involving unregulated cell growth, cell-cell and cellmatrix interactions, cell adhesion, angiogenesis, and growth of new cancer colonies [1]. During these steps, the expression level of some genes is altered. Numerous studies have shown that in addition to sensing the extracellular environment, integrins are involved in various intracellular pathways, including cell adhesion, migration, polarity, survival, growth and death [3,5,6], suggesting their important role in cancer [4]. Integrins were shown to be differentially expressed during tumor growth and progression, making them potential targets for cancer diagnosis and therapy [3,5,6]
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