title: BRAF and epithelial-mesenchymal transition in primary cutaneous melanoma: a role for Snail and E-cadherin?
abstract: In vitro studies in melanoma indicate that up-regulation of the transcriptional repressor Snail occurs with a concomitant decrease of its target E-cadherin, both hallmarks of epithelial-mesenchymal transition-an association not established in vivo. We sought to elucidate the relationship between BRAF, Snail, E-cadherin, and established histopathologic prognosticators in primary cutaneous melanoma. Archived annotated samples with a diagnosis of primary cutaneous melanoma were retrieved (n = 68 cases; 34 BRAF mutant and 34 BRAF wild type) and immunohistochemically stained for Snail and E-cadherin protein expression. A semiquantitative scoring system was used. Multivariate logistic analysis was used to control confounders of BRAF. Snail expression was significantly associated only with ulceration (42% versus 13%; P = .02). E-cadherin expression was present in 26% of BRAF mutant and 71% of BRAF wild-type cases (P = .0003). Loss of E-cadherin expression was associated with female sex (60% versus 34%; P = .05), BRAF mutation (74% versus 29%; P = .0003), thickness greater than or equal to 1 mm (68% versus 32%; P = .004), mitosis (63% versus 25%; P = .007), and ulceration (75% versus 44%; P = .05). BRAF mutation was associated with male sex (60% versus 30%; P = .02), Breslow thickness (P = .007), thickness greater than or equal to 1 mm (68% versus 29%; P = .002), and ulceration (75% versus 42%; P = .02). Snail expression did not correlate with loss of E-cadherin expression (47% versus 53%; P = .79). After controlling for potential confounding, BRAF mutation was associated with loss of E-cadherin (adjusted odds ratio, 8.332; 95% confidence interval, 2.257-30.757; P = .0015) and Breslow thickness greater than 1 mm (adjusted odds ratio, 7.360; 95% confidence interval, 1.534-35.318; P = .0126). Our findings, indicating that mutant BRAF represses E-cadherin expression, implicating a catalytic role for BRAF in epithelial-mesenchymal transition.
authors.affiliation: University of Florida College of Medicine, Gainesville, FL, 32603. Electronic address: Brendonmitchell7@gmail.com.
authors.forename: Brendon
authors.initials: B
authors.lastname: Mitchell
authors.affiliation: School of Public Health, Boston University School of Medicine, Boston, MA 02118. Electronic address: nleone@bu.edu.
authors.forename: Dominick A
authors.initials: DA
authors.lastname: Leone
authors.affiliation: Boston University School of Medicine, Boston, MA 02118. Electronic address: j.kyle.feller@gmail.com.
authors.forename: John K
authors.initials: JK
authors.lastname: Feller
authors.affiliation: Department of Pathology, Boston University School of Medicine, Boston, MA 02118. Electronic address: shiyang@bu.edu.
authors.forename: Shi
authors.initials: S
authors.lastname: Yang
authors.affiliation: Dermatopathology Section, VA Consolidated Laboratories, Department of Pathology and Laboratory Medicine (113), West Roxbury, MA 02132. Electronic address: me@meeramahalingam.com.
authors.forename: Meera
authors.initials: M
authors.lastname: Mahalingam
mesh_terms: D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001706:Biopsy; D015820:Cadherins / Q000032:analysis*; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015999:Multivariate Analysis; D009154:Mutation; D016017:Odds Ratio; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000071250:Snail Family Transcription Factors / Q000032:analysis*
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; C513384:CDH1 protein, human; D015820:Cadherins; D000071250:Snail Family Transcription Factors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; E-cadherin; Epithelial-mesenchymal transition; Primary cutaneous melanoma; Snail