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

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 foun...

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Published in:	International journal of cancer Vol. 131; no. 1; pp. 83 - 94
Main Authors:	Zhang, Yong-Qiang, Bianco, Andrea, Malkinson, Alvin M., Leoni, Vera Piera, Frau, Gianni, De Rosa, Nicolina, André, Pierre-Alain, Versace, Renato, Boulvain, Michel, Laurent, Geoffrey J., Atzori, Luigi, Irminger-Finger, Irmgard
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-07-2012 Wiley-Blackwell Wiley Subscription Services, Inc
Subjects:	Adult Aged Alternative Splicing Animals BARD1 Biological and medical sciences biomarker Biomarkers, Tumor - chemistry Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Biopsy BRCA1 BRCA1 protein BRCA1 Protein - genetics BRCA1 Protein - metabolism Cancer Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - mortality Cell Line, Tumor Cell proliferation differential splicing Disease Progression Epitopes Female Gene expression Humans Immunohistochemistry Invasiveness Isoforms Localization Lung - metabolism Lung cancer Lung Neoplasms - genetics Lung Neoplasms - metabolism Male Medical prognosis Medical research Medical sciences Mice Mice, Inbred BALB C Middle Aged mRNA Neoplasm Invasiveness - genetics Non-small cell lung carcinoma NSCLC Ovarian cancer Pneumology Protein Isoforms - chemistry Protein Isoforms - genetics Protein Isoforms - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism Small cell lung carcinoma Statistical analysis Survival Analysis Tumor Suppressor Proteins - chemistry Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - immunology Tumor Suppressor Proteins - metabolism Tumors Tumors of the respiratory system and mediastinum Ubiquitin-protein ligase Ubiquitin-Protein Ligases - chemistry Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - immunology Ubiquitin-Protein Ligases - metabolism BARD1 Lung disease Alternative splicing Molecular form NSCLC Respiratory disease Lung cancer Biological marker isoforms Malignant tumor BRCA1 non-small cell lung carcinoma biomarker Survival Cancerology differential splicing Bronchus disease Predictive factor BRCA1 gene Cancer Tumor suppressor gene
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Summary:	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.
Bibliography:	USPHS - No. CA132557 ark:/67375/WNG-2P44B066-Q SNRF - No. 31003A-122353 ArticleID:IJC26346 istex:9BBFD7F09D0DC31AEC90CF749E615F7DC26E8FF6 Oncosuisse - No. KLS-01962-10-2006 Tel: [+41‐22‐3824‐327] Irmgard Irminger‐Finger is a shareholder of Y.‐Q.Z and A.B. contributed equally to this work a company dedicated to developing tests for cancer detection. BARD1AG ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0020-7136 1097-0215
DOI:	10.1002/ijc.26346