The cell-cell adhesion molecule E-cadherin is stabilized by linking intracellularly with the actin cytoskeleton through PP2A-mediated recruitment of IQGAP1 to Racl-bound E-cadherin-catenins complex in nonmalignant HME cells. However, little is known about the dysfunction of E-cadherin by loss or reduced expression of PP2A in human breast cancer cells. We report here that both human breast cancer MDA-MB-231 and MCF-7 cells were deficient in expression of the PP2A-A protein and lost the IQGAP1 recruitment to Racl-bound catenins. In MDA-MB-231 cells, E-cadherin was also deficient. Immunohistochemical analysis of the normal-carcinoma matched human breast tissue arrays revealed that PP2A-A was expressed in 96% of normal tissue specimens but not in 57% of carcinoma specimens. Expression of E-cadherin in MCF-7 cells was 1.5-fold higher than that in HME cells, however, 80% of E-cadherin was endocytosed and incompletely anchored to F-actin. Therefore, we propose that the dysfunction of E-cadherin due to its endocytosis may occur in some proportion of human breast carcinomas in which the PP2A-A protein is lost or significantly reduced. (c) 2006 Elsevier Inc. All rights reserved.