title: 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).
authors.affiliation: Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Ponce
authors.affiliation: Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California.|College of Pharmacy, Touro University of California, Vallejo, California.
authors.forename: Maggie C
authors.initials: MC
authors.lastname: Louie
authors.affiliation: Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, California.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Sevigny
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D015820:Cadherins / Q000378:metabolism*; D002104:Cadmium / Q000009:adverse effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D059748:Proteolysis / Q000187:drug effects*; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015820:Cadherins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D002104:Cadmium
keywords: E-cadherin; breast cancer; cadmium; β-catenin