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 b-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 0 -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.

Comprehensive genetic and functional characterization of IPH‐926: a novel CDH1‐null tumour cell line from human lobular breast cancer

“…Loss of E-cadherin expression is accompanied by a loss of β-catenin expression and a diffuse scattering of Tables 1 and 2 the E-cadherin binding protein p120-catenin over the whole cytoplasm in both cell lines ( Figure 5C). Aberrant cytoplasmic localization of p120-catenin, which is virtually never observed in ductal mammary carcinomas [4], was also clearly evident in IPH-926 tumours grown in SCID mice and the ILBC of the corresponding patient ( Figure 5D). Both cell lines are also ErbB2-negative ( Figure 5A).…”

“…They lack expression of E-cadherin [2] and this serves as a supportive parameter in their clinical diagnosis [1]. Loss of E-cadherin expression is always accompanied by a loss of β-catenin expression and is frequently associated with aberrant cytoplasmic localization of the Ecadherin binding protein p120-catenin in ILBCs [3,4].…”

In breast carcinoma dysadherin expression is correlated with invasiveness but not with E-cadherin

“…This LOH definitely accompanies mutations in cases of invasive lobular carcinoma, however, the classic pattern of LOH coupled with inactivating mutations in lobular carcinoma in situ has not been confirmed. In the other 50% loss of E-cadherin is attributed to epigenetic events, with hypermethylation of the E-cadherin promoter region at CpG islands being one of the most important ones and possibly occurring very early, even at the stage of atypical lobular hyperplasia (Sarrio et al, 2004;Shibata et al, 2004;Knudsen and Wheelock, 2005;Mastracci et al, 2005).…”

The biological and clinical characteristics of breast carcinoma with mixed ductal and lobular morphology

“…Although treatment for stage-matched ductal versus lobular carcinomas is similar [9], several studies have shown that ILC is a distinct entity of breast cancer that differs from IDC not only in histological and clinical features [10,11] but also in the risk factors [12], genomic profiles [13], global transcription programs [14], immunophenotype [15] and response to systemic therapy [11,16,17]. Such studies suggest that lobular tumour development and progression may follow a distinct pathway from ductal tumours.…”