E-cadherin alterations in atypical lobular hyperplasia and lobular carcinoma in situ of the breast

Abstract

Tumor development from an early lesion through to invasive disease is not a clearly defined progression in the breast. Studies of invasive lobular carcinoma have reported mutations, loss of heterozygosity (LOH) and loss of protein expression in epithelial (E)-cadherin, a protein involved in cell adhesion. Our study examines in situ lobular neoplastic lesions without concurrent invasive carcinoma for E-cadherin gene alterations and protein expression, beta-catenin, alpha-catenin and p120-catenin protein expression, and LOH at the chromosome 16q locus, with the goal of determining the events occurring at the stage of lobular neoplasia. In all, 13 atypical lobular hyperplasia lesions and 13 lobular carcinoma in situ lesions from archived cases were examined. E-cadherin sequence alterations were evaluated using single strand conformation polymorphism and DNA sequencing, and PCR-based LOH analysis was carried out for the 16q locus. Using immunohistochemistry, we assessed protein expression. A total of 23 of 24 lesions evaluated by immunohistochemistry were negative for both E-cadherin and beta-catenin protein expression, and 21 of 23 lesions were negative for alpha-catenin. Cytoplasmic (rather than membrane) localization of p120-catenin was observed in 20 of 21 cases. Lobular carcinoma in situ cases were characterized by mutations; however, atypical lobular hyperplasia cases were not. LOH at 16q was an infrequent event. From our study, we conclude that an altered E-cadherin adhesion complex is an early event affecting atypical lobular hyperplasia as well as lobular carcinoma in situ and occurs prior to progression to invasive disease. However, the loss of protein expression is accompanied by E-cadherin DNA alterations in lobular carcinoma in situ but not in atypical lobular hyperplasia. These cases lacking both protein expression and gene alterations suggest that another mechanism is involved, possibly as early as at the hyperplastic stage, causing silencing of the E-cadherin complex.

Loss of expression of chromosome 16q genes DPEP1 and CTCF in lobular carcinoma in situ of the breast

“…We used CDH1 as a positive control as it has previously been recognised as a TSG in lobular carcinomas [5,9,13,25]. The results presented here further support previous studies [9,[26][27][28] in suggesting that CDH1 is a TSG in LCIS, as immunohistochemistry and RT-PCR showed almost complete absence of expression compared with normal breast lobules. However, in vitro evidence suggests that the loss of E-cadherin alone is not responsible for tumorigenesis and that it has been proposed that additional TSG at 16q are required to complete the multistep process.…”

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

“…This loss is an early event affecting not only lobular carcinoma in situ but even atypical lobular neoplasia (Mastracci et al, 2005). This silencing of E-cadherin is attributed to genetic as well as epigenetic events (Knudsen and Wheelock, 2005;Mastracci et al, 2005).…”

“…This loss is an early event affecting not only lobular carcinoma in situ but even atypical lobular neoplasia (Mastracci et al, 2005). This silencing of E-cadherin is attributed to genetic as well as epigenetic events (Knudsen and Wheelock, 2005;Mastracci et al, 2005). In approximately 50% of lobular carcinomas loss of E-cadherin involves LOH at the chromosomal region of 16q, which includes the E-cadherin gene CDH1 locus and mutations in the remaining allele (Kanai et al, 1994;Vos et al, 1997;Huiping et al, 1999;Knudsen and Wheelock, 2005;Mastracci et al, 2005).…”

“…Today, there is a plethora of molecular genetic data that indicate differences in pathogenesis between the various types of breast carcinomas and thus support their categorisation, to the patient benefit. The demonstration of lack of E-cadherin expression in lobular neoplasms has had a sound impact with practical applications (Mastracci et al, 2005) In about half of lobular carcinomas, loss of E-cadherin involves genetic changes, that is loss of heterozygosity (LOH) at 16q22.1, while in the other half epigenetic events are involved (Knudsen and Wheelock, 2005;Mastracci et al, 2005). Ductal carcinomas, on the other hand, express E-cadherin, albeit in reduced levels and/or in abnormal cellular locations (Knudsen and Wheelock, 2005).…”

“…Reduction/loss of E-cadherin has been associated with the development and progression of many epithelial neoplasms. Aberrant E-cadherin expression (heterogeneous, cytoplasmic, or absent) has been detected immunohistochemically in several cancers, including head and neck carcinoma, gastric adenocarcinoma, lobular breast carcinoma, lung cancer, colorectal carcinoma, prostate adenocarcinoma, pancreatic, and bladder cancer (Becker et al, 1994;Hirohashi, 1998;Chang et al, 2002;Charalabopoulos et al, 2002Charalabopoulos et al, , 2004Hirohashi and Kanai, 2003;Mastracci et al, 2005;Massarelli et al, 2005). In the vast majority of these neoplasms such expression has been associated with poor differentiation, increased metastatic potential and poor prognosis.…”