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P-Cadherin Overexpression Is an Indicator of Clinical Outcome in Invasive Breast Carcinomas and Is Associated with CDH3 Promoter Hypomethylation

Authors' Affiliations: ¹ Institute of Pathology and Molecular Immunology of Porto University (IPATIMUP); ² Department of Genetics, Portuguese Oncology Institute of Porto; ³ School of Health Sciences - Fernando Pessoa University, Porto; ⁴ Medical Faculty, Porto University, Porto; and ⁵ School of Health Sciences, University of Minho, Braga, Portugal

Requests for reprints: Joana Paredes, Institute of Pathology and Molecular Immunology of Porto University, Rua Dr. Roberto Frias s/n 4200-465 Oporto, Portugal. Phone: 351-22557-0700; Fax: 351-22557-0799; E-mail: jparedes{at}ipatimup.pt.

Purpose: P-cadherin overexpression has been reported in breast carcinomas, where it was associated with proliferative high-grade histological tumors. This study aimed to analyze P-cadherin expression in invasive breast cancer and to correlate it with tumor markers, pathologic features, and patient survival. Another purpose was to evaluate the P-cadherin promoter methylation pattern as the molecular mechanism underlying this gene regulation.

Experimental Design: Using a series of invasive breast carcinomas, P-cadherin expression was evaluated and correlated with histologic grade, estrogen receptor, MIB-1, and p53 and c-erbB-2 expression. In order to assess whether P-cadherin expression was associated with changes in CDH3 promoter methylation, we studied the methylation status of a gene 5'-flanking region in these same carcinomas. This analysis was also done for normal tissue and for a breast cancer cell line treated with a demethylating agent.

Results: P-cadherin expression showed a strong correlation with high histologic grade, increased proliferation, c-erbB-2 and p53 expression, lack of estrogen receptor, and poor patient survival. This overexpression can be regulated by gene promoter methylation because the 5-Aza-2'-deoxycytidine treatment of MCF-7/AZ cells increased P-cadherin mRNA and protein levels. Additionally, we found that 71% of P-cadherin-negative cases showed promoter methylation, whereas 65% of positive ones were unmethylated (P = 0.005). The normal P-cadherin-negative breast epithelial cells showed consistent CDH3 promoter methylation.

Conclusions: P-cadherin expression was strongly associated with tumor aggressiveness, being a good indicator of clinical outcome. Moreover, the aberrant expression of P-cadherin in breast cancer might be regulated by gene promoter hypomethylation.

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