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).