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

Article Article scientifique Article BARD1: an independent predictor of survival in non-small cell lung cancer eng 2012 author Zhang Yong Qiang 682792 author Bianco Andrea author Malkinson Alvin M author Leoni Vera Piera author Frau Gianni author De Rosa Nicolina author Andre Pierre-Alain 745001 author Versace Renato author Boulvain Michel 118156 author Laurent Geoffrey J author Atzori Luigi author Irminger Irmgard 27662 83-94 10.1002/ijc.26346 21815143 0020-7136 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. Adult Aged Alternative Splicing Animals BRCA1 Protein/genetics/metabolism Carcinoma, Non-Small-Cell Lung/genetics/metabolism/mortality Cell Line, Tumor Disease Progression Female Humans Lung/metabolism Lung Neoplasms/genetics/metabolism Male Mice Mice, Inbred BALB C Middle Aged Neoplasm Invasiveness/genetics Protein Isoforms/chemistry/genetics/metabolism RNA, Messenger/genetics/metabolism Survival Analysis Tumor Markers, Biological/chemistry/genetics/metabolism Tumor Suppressor Proteins/chemistry/genetics/immunology/metabolism Ubiquitin-Protein Ligases/chemistry/genetics/immunology/metabolism Dewey 618 58 Département de pédiatrie, gynécologie et obstétrique 223 false 213 Martinez De Tejada Begona 272 International journal of cancer 131 1 92dff84c-66c4-4776-b456-2909e83208fc Article (Published version) Restricted Zhang-2012-BARD1_ an independen.pdf 1881310 application/pdf restrictedAccess Faculté de médecine / Section de médecine clinique / Département de pédiatrie, gynécologie et obstétrique

Title	Published in	Year	Views	Downloads

BARD1: an independent predictor of survival in non-small cell lung cancer	International journal of cancer	2012	659	0
Analyse de l'expression de BARD1 dans le cancer du poumon et le cancer colorectal		2010	1,208	609

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Zhang, Yong Qiang