1. BARD1: an independent predictor of survival in non-small cell lung cancer
- Author
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Vera Piera Leoni, Nicolina De Rosa, Renato Versace, Pierre-Alain André, Irmgard Irminger-Finger, Alvin M. Malkinson, Michel Boulvain, Andrea Bianco, Geoffrey J. Laurent, Gianni Frau, Yong Qiang Zhang, Luigi Atzori, Zhang, Yq, Bianco, Andrea, Malkinson, Am, Leoni, Vp, Frau, G, Rosa, Nd, André, Pa, Versace, R, Boulvain, M, Laurent, Gj, Atzuri, L, and IRMINGER FINGER, I.
- Subjects
Male ,Ubiquitin-Protein Ligase ,Cancer Research ,Lung Neoplasms ,Tumor initiation ,Lung/metabolism ,NSCLC ,Epitope ,Tumor Suppressor Proteins/chemistry/genetics/immunology/metabolism ,Mice ,0302 clinical medicine ,Protein Isoforms/chemistry/genetics/metabolism ,Carcinoma, Non-Small-Cell Lung ,Protein Isoforms ,Lung ,0303 health sciences ,Mice, Inbred BALB C ,ddc:618 ,BRCA1 Protein ,isoform ,Middle Aged ,3. Good health ,Tumor Markers, Biological/chemistry/genetics/metabolism ,Oncology ,030220 oncology & carcinogenesis ,Disease Progression ,Immunohistochemistry ,biomarker ,Female ,Survival Analysi ,Human ,Gene isoform ,Adult ,RNA, Messenger/genetics/metabolism ,Ubiquitin-Protein Ligases ,Biology ,Carcinoma, Non-Small-Cell Lung/genetics/metabolism/mortality ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,BARD1 ,Animals ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,Lung cancer ,030304 developmental biology ,Aged ,Neoplasm Invasivene ,Tumor Suppressor Protein ,Animal ,differential splicing ,Tumor Suppressor Proteins ,Protein Isoform ,Lung Neoplasms/genetics/metabolism ,Ubiquitin-Protein Ligases/chemistry/genetics/immunology/metabolism ,medicine.disease ,BRCA1 ,Survival Analysis ,Lung Neoplasm ,Alternative Splicing ,BRCA1 Protein/genetics/metabolism ,Cancer cell ,Cancer research ,Neoplasm Invasiveness/genetics ,Ovarian cancer ,Immunostaining - 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.
- Published
- 2011