Coexpression of e-cadherin and cytokeratin 18 is decreased by estrogen or mutant p53 in human breast carcinoma

2844

Introduction. Abrogation of the p53 tumor suppressor function by mutation or dysfunction is a major feature of cancer development and may result in decreased therapeutic response . Also, the oestrogen receptor status of breast tumours predicts prognosis and response to hormonal treatment. This report investigates whether oestrogen signaling or introducing a dominant negative human p53 mutant 175His transgene defective in transactivation , into wild-type p53-containing MCF-7 breast carcinoma affect expression of proteins regulating epithelial intercellular adhesion like E-cadherin (Oesterreich S. et al, Cancer Res. 2003 ;63:5203) or differentiation like cytokeratin 18 (CK18), a marker for differentiated luminal epithelium, whose down-regulation has been linked to breast cancer tumor progression (Woelfle U.et al, Clin Cancer Res. 2004 ;10:2670). Methods and Results. Immune blotting showed that introducing mutant p53 decreased both E-cadherin and CK 18 compared to their significant expression in wt p53 MCF-7 breast carcinoma . In the latter cells, immune fluorescence revealed CK18 expression preferentially in areas where extensive cell-cell contacts were established, implying that coexpression of these 2 proteins is important in maintaining epithelial shape and intercellular organization. Laser scanning cytometry (LSC) revealed 2 populations with intermediate and high levels of CK18, but no high CK18 population in mutant p53 MCF-7 cells. Coexpression of CK18 and E-cadherin without colocalization was evidenced by LSC , being evidently greater in wt p53 MCF-7 cells compared with to their genetically matched counterparts with mutant p53. However, a decrease in this coexpression was also evident in wt p53 MCF-7 carcinoma exposed to estrogen ,through decreased E-cadherin without a comparable effect on CK 18. Conclusions. Our results suggest that a decrease in CK18 and E-cadherin coexpression resulting from estrogenic- or mutant p53 -oncogenic signalling, is likely to lower intercellular adhesion and promote cytoskeletal plasticity, thereby increasing motility in epithelial tumors. We propose that quantitating loss in coexpression of these 2 markers may be helpful in assessing breast cancer progression.