Acute and chronic cadmium exposure promotes E‐cadherin degradation in MCF7 breast cancer cells

Abstract

Cadmium is an environmental carcinogen that usually enters the body at minute concentrations through diet or cigarette smoke and bioaccumulates in soft tissues. In past studies, cadmium has been shown to contribute to the development of more aggressive cancer phenotypes including increased cell migration and invasion. This study aims to determine if cadmium exposure-both acute and chronic-contributes to breast cancer progression by interfering with the normal functional relationship between E-cadherin and β-catenin. An MCF7 breast cancer cell line (MCF7-Cd) chronically exposed to 10(-7) M CdCl2 was previously developed and used as a model system to study chronic exposures, whereas parental MCF7 cells exposed to 10(-6) M CdCl2 for short periods of time were used to study acute exposures. Cadmium exposure of MCF7 cells led to the degradation of the E-cadherin protein via the ubiquitination pathway. This resulted in fewer E-cadherin/β-catenin complexes and the relocation of active β-catenin to the nucleus, where it interacted with transcription factor TCF-4 to modulate gene expression. Interestingly, only cells chronically exposed to cadmium showed a significant decrease in the localization of β-catenin to the plasma membrane and an increased distance between cells. Our data suggest that cadmium exposure promotes breast cancer progression by (1) down-regulating E-cadherin, thus decreasing the number of E-cadherin/β-catenin adhesion complexes, and (2) enhancing the nuclear translocation of β-catenin to increase expression of cancer-promoting proteins (i.e., c-Jun and cyclin D1).

Exposure to low dose cadmium enhances FL83B cells proliferation through down-regulation of caspase-8 by DNA hypermethylation

“…43,44 In our present work, repeated Cd exposures clearly enhanced malignant progression of FL83B cells, as assessed by the rate of regional invasiveness and distant metastases. 43,44 In our present work, repeated Cd exposures clearly enhanced malignant progression of FL83B cells, as assessed by the rate of regional invasiveness and distant metastases.…”

Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling

“…Several studies report a strong correlation between E-cadherin loss and the initiation and progression of tumors [26, 54]. The cytoplasmic domain of E-cadherin is attached to actin microfilaments via two other molecules, α- and β-catenin [55]. Disruption of these E-cadherin homotypic interactions results in the release of β -catenin from E-cadherin and subsequent translocation of β -catenin into the nucleus; the nuclear β-catenin associates with TCF4 (a member of transcription factor family) to form a β-catenin/TCF complex and activates the transcription of genes involved in cancer initiation, progression and metastasis such as c-Myc, and uPAR [26].…”

Serine protease modulation of Dependence Receptors and EMT protein expression

“…34,76,78,84,85 The effect is believed to follow the dissolution of the adherens junctions, the removal of E-cadherin and the consequent release of bound β-catenin into the cytoplasm: E-cadherin exerts a stabilising influence on the levels of β-catenin. 16,[86][87][88] Altered expression or activity of β-catenin has been implicated in regulating proliferation 28,84 and oncogenesis 22,33,75,[89][90][91] being proposed as a 'co-factor' in the initiation of EMT. 92,93 Inhibition of the Wnt/β-catenin pathway inhibits cancer cell proliferation 31,94,95 although others have linked β-catenin activation to reduced growth and increased differentiation.…”