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BARD1: an independent predictor of survival in non-small cell lung cancer

Bianco, Andrea
Malkinson, Alvin M
Leoni, Vera Piera
Frau, Gianni
De Rosa, Nicolina
Versace, Renato
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Published in International journal of cancer. 2012, vol. 131, no. 1, p. 83-94
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.
Keywords AdultAgedAlternative SplicingAnimalsBRCA1 Protein/genetics/metabolismCarcinoma, Non-Small-Cell Lung/genetics/metabolism/mortalityCell Line, TumorDisease ProgressionFemaleHumansLung/metabolismLung Neoplasms/genetics/metabolismMaleMiceMice, Inbred BALB CMiddle AgedNeoplasm Invasiveness/geneticsProtein Isoforms/chemistry/genetics/metabolismRNA, Messenger/genetics/metabolismSurvival AnalysisTumor Markers, Biological/chemistry/genetics/metabolismTumor Suppressor Proteins/chemistry/genetics/immunology/metabolismUbiquitin-Protein Ligases/chemistry/genetics/immunology/metabolism
PMID: 21815143
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Research group Martinez De Tejada Begona (272)
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ZHANG, Yong Qiang et al. BARD1: an independent predictor of survival in non-small cell lung cancer. In: International journal of cancer, 2012, vol. 131, n° 1, p. 83-94. doi: 10.1002/ijc.26346 https://archive-ouverte.unige.ch/unige:31818

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Deposited on : 2013-12-05

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