Cadmium stimulates metastasis-associated phenotype in triple-negative breast cancer cells through integrin and β-catenin signaling

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Abstract

Cadmium (Cd) is a carcinogenic heavy metal which is implicated in breast cancer development. While the mechanisms of Cd-induced breast cancer initiation and promotion have been studied, the molecular processes involved in breast cancer progression remain to be investigated. The purpose of the present study was to evaluate the influence of Cd on metastasis-associated phenotypes, such as cell adhesion, migration, and invasion in triple-negative breast cancer cells. Treatment of MDA-MB-231 cells with 1 μM Cd increased cell spreading and cell migration. This was associated with the activation of integrin β1, FAK, Src, and Rac1. Treatment with Cd also inhibited GSK3β activity and induced T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription, indicating the involvement of β-catenin signaling. Furthermore, treatment with 3 μM Cd for 4 weeks increased the expression of β-catenin and enhanced TCF/LEF-mediated transcription. Furthermore, enhanced expressions of integrins α5 and β1, paxillin, and vimentin indicated that prolonged Cd treatment reorganized the cytoskeleton, which aided malignancy, as evidenced by enhanced matrix metalloprotease 2/9 (MMP2/9) secretion and cell invasion. Prolonged Cd treatment also caused an increase in cell growth. Together, these results indicate that Cd alters key signaling processes involved in the regulation of cytoskeleton to enhance cancer cell migration, invasion, adhesion, and proliferation.

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