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Cytoplasmic localization of p120ctn and E-cadherin loss characterize lobular breast carcinoma from preinvasive to metastatic lesions

Abstract

Accumulating evidences indicate that p120 catenin, a member of the E-cadherin (E-CD)/catenin adhesion complex, plays a role in tumor invasion. To establish the expression pattern of p120 in breast cancer, we analysed 326 breast tissue biopsies by tissue microarray. Most of the lobular tumors (88%) showed exclusive cytoplasmic localization, and 6% of them also had p120 nuclear staining. Cytoplasmic p120 strongly associated with complete loss of E-CD and β-catenin not only in lobular carcinoma and its metastases but also in atypical lobular hyperplasias. In the latter, loss of heterozygosity of E-CD gene was also observed. Complete loss of E-CD and cytoplasmic and nuclear p120 staining was also observed in primary lobular cancer cell cultures generated by us. In ductal tumors, by contrast, reduction of p120 and E-CD in membrane was very common (57 and 53%, respectively), whereas cytoplasmic p120 staining was rarely seen. This simultaneous reduction of membranous E-CD and p120 was not associated with increased Src kinase activity. To demonstrate that cytoplasmic p120 localization was a consequence of the absence of E-CD, the endogenous E-CD was re-expressed in MDA-231 cells by 5-Aza-2′-deoxycytidine (5Aza) treatment. After treatment, p120 shifted from the cytoplasm to the membrane, where it colocalized with endogenous E-CD. Additionally, suppressing E-CD expression in Madin–Darby canine kidney cells by stable transfection of the transcriptional repressors Snail, E47 or Slug, provokes p120 cytoplasmic localization and p120 isoform switching. In conclusion, abnormal cytoplasmic and nuclear localization of p120, which are mediated by the absence of E-CD, characteristically occur in the early stages of lobular breast cancer and are maintained during tumor progression to metastasis. Consequently, p120 may be an important mediator of the oncogenic effects derived from E-CD inactivation, including enhanced motility and invasion, in lobular breast cancer.

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Acknowledgements

We thank Dr Albert Reynolds (Vanderbilt University, Nashville, TN, USA) for providing 6H11 mAb. We are also grateful to Ester Martín-Villar (IIB, CSIC, Madrid, Spain) for providing some cell lines, María Montoya (Biotechnology Programme, CNIO) for helping with immunofluorescence experiments, the CNIO immunohistochemical Unit, and Raquel Marcos for expert technical assistance. We also thank the Spanish National Tumor Bank and the Pathology Departments of the following Spanish Hospitals: ‘La Paz’, ‘Puerta de Hierro’, ‘Doce de Octubre’, and ‘Clínico San Carlos’ for providing fresh tumor tissue. David Sarrió is a recipient of a research grant from the Fondo de Investigación Sanitaria (BEFI, 01/9132), Spain.

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Correspondence to José Palacios.

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Sarrió, D., Pérez-Mies, B., Hardisson, D. et al. Cytoplasmic localization of p120ctn and E-cadherin loss characterize lobular breast carcinoma from preinvasive to metastatic lesions. Oncogene 23, 3272–3283 (2004). https://doi.org/10.1038/sj.onc.1207439

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