Cadherin–catenin complex dissociation in lobular neoplasia of the breast
- 576 Downloads
E-cadherin (E-CD) inactivation with loss of E-CD-mediated cell adhesion is the hallmark of lesions of the lobular phenotype. E-CD is typically absent by immunohistochemistry in both lobular carcinoma in situ (LCIS) and invasive lobular lesions, suggesting it occurs early in the neoplastic process. In laboratory models, downstream post-transcriptional modifiers such as TWIST and SNAIL contribute to the dissociation of the intracellular component of the cadherin–catenin complex (CCC), resulting in tumor progression and invasion. We hypothesized that complete CCC dissociation may play a role in lobular neoplasia progression. Here we explore the relationship between loss of E-CD and dissociation of the CCC in pure LCIS and LCIS associated with invasive cancer. Fresh-frozen tissues were obtained from 36 patients undergoing mastectomy for pure LCIS (n = 11), LCIS with ILC (n = 18) or LCIS with IDC (n = 7). Individual lesions were subject to laser-capture microdissection and gene-expression analysis (Affymetrix HG-U133A 2.0). Immunohistochemistry for ER,PR,HER2, E-CD,N-CD,α-,β-, and phosphoβ-catenin, TWIST, and SNAIL were evaluated in normal, in situ, and invasive components from matched formalin-fixed paraffin-embedded samples (n = 36). CCC-dissociation was defined as negative membranous E-CD, α- and β-catenin expression. E-CD was negative in all LCIS and ILC lesions, and positive in all normal and IDC lesions. Membranous α and β-catenin expressions decreased with the transition from LCIS to ILC (pure LCIS 82%; LCIS w/ILC 28%; ILC 0%), while TWIST expression increased (pure LCIS low; LCIS w/ILC moderate; ILC high). Gene expression paralleled IHC-staining patterns with a stepwise downregulation of E-CD, α and β-catenins from normal to LCIS to invasive lesions, and increasing expression of TWIST from normal to LCIS to ILC. Loss of E-CD expression is an early event in lobular neoplasia. Decreasing membranous catenin expression in tandem with increasing levels of TWIST across the spectrum of lobular lesions suggests that CCC dissociation is a progressive process.
KeywordsLobular carcinoma E-cadherin Catenin Dissociation Gene expression
Funding for this study was provided by the Breast Cancer Alliance, the Geoffrey Beene Cancer Research Center, the Association of Women Surgeons, and the Society of Surgical Oncology.
Conflict of interest
The authors report no conflicts of interest. The authors have control of all primary data and agree to allow the journal to review the data if requested.
- 15.Rahman N, Stone JG, Coleman G, Gusterson B, Seal S, Marossy A, Lakhani SR, Ward A, Nash A, McKinna A, A’Hern R, Stratton MR, Houlston RS (2000) Lobular carcinoma in situ of the breast is not caused by constitutional mutations in the E-cadherin gene. Br J Cancer 82:568–570PubMedCrossRefGoogle Scholar
- 21.Smyth GK (2004) Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol 3:3Google Scholar
- 23.Abdel-Fatah TM, Powe DG, Hodi Z, Lee AH, Reis-Filho JS, Ellis IO (2007) High frequency of coexistence of columnar cell lesions, lobular neoplasia, and low grade ductal carcinoma in situ with invasive tubular carcinoma and invasive lobular carcinoma. Am J Surg Pathol 31:417–426PubMedCrossRefGoogle Scholar
- 25.Abdel-Fatah TM, Powe DG, Hodi Z, Reis-Filho JS, Lee AH, Ellis IO (2008) Morphologic and molecular evolutionary pathways of low nuclear grade invasive breast cancers and their putative precursor lesions: further evidence to support the concept of low nuclear grade breast neoplasia family. Am J Surg Pathol 32:513–523PubMedCrossRefGoogle Scholar
- 29.Lombaerts M, van Wezel T, Philippo K, Dierssen JW, Zimmerman RM, Oosting J, van Eijk R, Eilers PH, van de Water B, Cornelisse CJ, Cleton-Jansen AM (2006) E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br J Cancer 94:661–671PubMedGoogle Scholar
- 34.Sarrio D, Moreno-Bueno G, Hardisson D, Sanchez-Estevez C, Guo M, Herman JG, Gamallo C, Esteller M, Palacios J (2003) Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability. Int J Cancer 106:208–215PubMedCrossRefGoogle Scholar