title: Cadherin-catenin complex dissociation in lobular neoplasia of the breast.
abstract: 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.
authors.affiliation: Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 300 E. 66th St., New York, NY 10065, USA. morroghm@mskcc.org
authors.forename: Mary
authors.initials: M
authors.lastname: Morrogh
authors.forename: Victor P
authors.initials: VP
authors.lastname: Andrade
authors.forename: Dilip
authors.initials: D
authors.lastname: Giri
authors.forename: Rita A
authors.initials: RA
authors.lastname: Sakr
authors.forename: Wooyul
authors.initials: W
authors.lastname: Paik
authors.forename: Li Xuan
authors.initials: LX
authors.lastname: Qin
authors.forename: Crispinita D
authors.initials: CD
authors.lastname: Arroyo
authors.forename: Edi
authors.initials: E
authors.lastname: Brogi
authors.forename: Monica
authors.initials: M
authors.lastname: Morrow
authors.forename: Tari A
authors.initials: TA
authors.lastname: King
mesh_terms: D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001943:Breast Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000032:analysis* / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D018275:Carcinoma, Lobular / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D042282:Microdissection; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D018193:Neoplasms, Complex and Mixed / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D009519:New York City; D009687:Nuclear Proteins / Q000032:analysis; D010766:Phosphorylation; D011379:Prognosis; D011446:Prospective Studies; D011485:Protein Binding; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000032:analysis; D051879:Twist-Related Protein 1 / Q000032:analysis; D051178:alpha Catenin / Q000032:analysis* / Q000235:genetics; D051176:beta Catenin / Q000032:analysis* / Q000235:genetics
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; D009687:Nuclear Proteins; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D051178:alpha Catenin; D051176:beta Catenin
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