The altered redistribution and accumulation of E‐cadherin as a dominant‐acting oncogene in inflammatory breast cancer (IBC)

Abstract

E‐cadherin, an adhesion protein within lateral junctions, is thought to function as a tumor suppressor in breast carcinomas and promote metastasis when its expression is lost by mutation, promoter methylation or repression by mediators of EMT. However in IBC, E‐cadherin is overexpressed circumferentially which accounts for the formation of the lymphovascular embolus, a structure efficient at metastasis and drug resistance. Our studies with a human IBC xenograft, MARY‐X, revealed that E‐cadherin transcripts were less than MCF‐7 and MCF‐10A (E‐cadherin positive lines) but the protein levels were 100 fold greater. We found E‐cadherin overexpressed because of altered degradation, redistribution and trafficking. Since previous studies had shown that E‐cadherin lysosomal targeting was mediated by the hepatocyte GF‐tyrosine kinase substrate (Hrs) and that v‐src activation of Rab7 depleted E‐cadherin in EMT, we investigated whether these genes might be decreased in MARY‐X and found this so. Since other Drosophila proteins, eg., sec10 mediated E‐cadherin trafficking from recycling endosomes to plasma membranes, we observed the human equivalent, exoC5, to be increased in MARY‐X. siRNA Rab 7 knockdown in MCF‐7 produced an increase in the 120 KD band of E‐cadherin as well as E‐cadherin intermediates. This suggested that altered E‐cadherin redistribution may be contributing to its oncogenic role in IBC.