A novel transcription factor, OB2‐1, is required for overexpression of the proto‐oncogene c‐erbB‐2 in mammary tumour lines

• Published in: The EMBO journal 1993-06, Vol.12 (6), p.2369-2375
• Main Authors: Hollywood, D.P., Hurst, H.C.
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological and medical sciences; Breast Neoplasms - metabolism; Cell Line; DNA, Neoplasm; DNA-Binding Proteins - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression; Humans; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Promoter Regions, Genetic; Protein-Tyrosine Kinases - biosynthesis; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Mas; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Proto-Oncogenes; Receptor, ErbB-2; RNA, Messenger - metabolism; Transcription Factors - metabolism; Transcription. Transcription factor. Splicing. Rna processing; Tumor Cells, Cultured
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1002/j.1460-2075.1993.tb05891.x

The c‐erbB‐2 receptor tyrosine kinase proto‐oncogene product is overexpressed in 20‐30% of breast carcinomas and this has been shown to correlate with poor prognosis. Previous analysis of tumour‐derived lines has demonstrated that although the c‐erbB‐2 gene is often amplified, overexpression can occur from a single‐copy gene. Moreover, whether or not the gene is amplified, overexpressing cells produce 6‐ to 8‐fold more mRNA per gene copy than low‐expressing cells. In this paper, we examine the possible mechanisms causing this deregulation of c‐erbB‐2 mRNA accumulation. Nuclear run‐on studies indicated that the extra mRNA accumulation was due to increased transcription of the gene in overexpressing cells. Promoter analyses using c‐erbB‐2 5′ flanking sequences linked to CAT showed that the promoter is more active in overexpressing cells. Coupling promoter deletion functional studies with footprinting experiments, using nuclear extracts derived from both low and overexpressing cells, allowed the identification of a DNA‐binding protein, OB2‐1, which is considerably more abundant in a range of overexpressing lines. We discuss the possible role of OB2‐1 in c‐erbB‐2 overexpression in breast tumour lines.