title: BARD1: an independent predictor of survival in non-small cell lung cancer.
abstract: BRCA1 mRNA overexpression is correlated with poor survival in NSCLC. However, BRCA1 functions depend on the interaction with BARD1 for its stability, nuclear localization and ubiquitin ligase activity. Expression of alternatively spliced BARD1 isoforms that lack the BRCA1-interaction domain was found upregulated and correlated with poor prognosis in breast and ovarian cancer. These BARD1 isoforms are essential for proliferation of cancer cells in vitro. We investigated whether BARD1 isoforms are expressed in NSCLC. While in lung tissues from healthy controls BARD1 expression was undetectable on the mRNA level and protein level, we found two novel isoforms in addition to previously identified mRNAs expressed in all NSCLC samples tested. Furthermore, the pattern of BARD1 isoform expression was similar in tumor and morphologically normal peri-tumor tissues, and only one novel isoform π was specifically upregulated in tumors. Immunohistochemistry revealed that all 100 NSCLC cases tested expressed isoform-specific BARD1 epitopes, while BARD1 expression was undetectable in biopsies from healthy controls. Statistical analysis showed that the expression of epitopes PVC and WFS, present on isoform π, or epitope WFS alone, expressed on isoforms π, κ and β, were significantly correlated with decreased patient survival. These findings were corroborated in a mouse model of chemically induced lung cancer. Immunostaining of mouse tumors showed that BARD1 epitopes PVC and WFS were specifically upregulated in invasive, but not in confined lung tumors. Thus, BARD1 isoforms might be involved in tumor initiation and invasive progression and might represent a novel prognostic marker for NSCLC.
authors.affiliation: Molecular Gynecology and Obstetrics Laboratory, Department of Gynecology and Obstetrics, University Hospitals Geneva, Geneva, Switzerland.
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Zhang
authors.forename: Andrea
authors.initials: A
authors.lastname: Bianco
authors.forename: Alvin M
authors.initials: AM
authors.lastname: Malkinson
authors.forename: Vera Piera
authors.initials: VP
authors.lastname: Leoni
authors.forename: Gianni
authors.initials: G
authors.lastname: Frau
authors.forename: Nicolina
authors.initials: N
authors.lastname: De Rosa
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: André
authors.forename: Renato
authors.initials: R
authors.lastname: Versace
authors.forename: Michel
authors.initials: M
authors.lastname: Boulvain
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Laurent
authors.forename: Luigi
authors.initials: L
authors.lastname: Atzori
authors.forename: Irmgard
authors.initials: I
authors.lastname: Irminger-Finger
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D020033:Protein Isoforms; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases