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 peritumor tissues, and only one novel isoform p 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 p, or epitope WFS alone, expressed on isoforms p, j and b, 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.Lung cancer is the leading cause of cancer death worldwide due to detection at an advanced stage and to inefficiency of resistance to treatment methods, other than surgery. Thus, insights into the etiology of lung cancer and its progression are urgently needed.Protein, RNA and microRNA profiles from lung tumors have been screened for potential drivers of lung cancer. [1][2][3][4] TP53 is the most frequently deleted or mutated gene in lung cancer, followed by components of the p53-ARF pathway. 5 Novel predictive and prognostic molecular markers in nonsmall-cell lung cancer (NSCLC) include DNA damage repair genes, such as ERCC1, RRM1 and BRCA1. 6 Upregulation of mRNA of the breast cancer predisposition gene BRCA1, correlated with reduced survival of NSCLC patients, is a predictive marker for response to treatment of NSCLC. 7,8 However, the mechanism behind BRCA1 mRNA expression and cancer outcome is not clear. BRCA1 is a tumor suppressor and expressed in many proliferating tissues, but its tumor suppressor functions depend on its interaction with the BRCA1-associated RING Domain 1 (BARD1) protein for stability, nuclear localization and for enhancing its ubiquitin

Expression of oncogenic BARD1 isoforms affects colon cancer progression and correlates with clinical outcome

“…To distinguish the expression of different exons of BARD1, we used four previously characterised antibodies (Irminger-Finger et al , 1998; Wu et al , 2006; Li et al , 2007; Zhang et al , 2012) (N19, PVC, WFS, and C20) recognising regions in exon 1 (N-terminus), end of exon 3 (after RING region), beginning of exon 4, and exon 11 (C-terminus) (Figure 1C), on adjacent tissue sections. We also investigated BRCA1 expression using an antibody against BRCA1.…”

Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview

“…Many breast and ovarian cancer cell lines and primary tumors exhibit high levels of cytosolic BRCA1. The RING finger element of BRCA1 mediates nuclear import by association with its binding partner, BRCA1-associated RING domain protein 1 (BARD1) [58]. The structure of the BRCA1/BARD1 heterodimer predicts that the BRCA1 NES lies within the RING finger domain that mediates shuttling of BRCA1 into the cytoplasm [59].…”

Cancer-Risk Module Identification and Module-Based Disease Risk Evaluation: A Case Study on Lung Cancer

“…For instance, MCM7 is a significant subunit of MCM complex, which could be a novel therapeutic target in lung cancer [58]. Another gene BARD1, whose isoforms may be related to tumor initiation and invasive progression, was a more suitable neoteric prognostic marker for non-small-cell lung cancer [59]. KIF4A might hold a promise for the development of anticancer drugs and cancer vaccines as well as a prognostic biomarker in clinic [60].…”