Altered promoter usage characterizes monoallelic transcription arising with ERBB2 amplification in human breast cancers
✍ Scribed by Christopher C. Benz; Vita Fedele; Fan Xu; Bauke Ylstra; David Ginzinger; Mamie Yu; Dan Moore; Rayna Kneuper Hall; Daynna J. Wolff; Mary L. Disis; Serenella Eppenberger-Castori; Urs Eppenberger; Francesco Schittulli; Stefania Tommasi; Angelo Paradiso; Gary K. Scott; Donna G. Albertson
- Publisher
- John Wiley and Sons
- Year
- 2006
- Tongue
- English
- Weight
- 270 KB
- Volume
- 45
- Category
- Article
- ISSN
- 1045-2257
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✦ Synopsis
Abstract
Analysis of a collection of human breast cancers (n = 150), enriched in ERBB2‐positive cases (n = 57) and involving tumor genotyping relative to population‐matched blood genotyping (n = 749) for a common ERBB____2 single nucleotide polymorphism Ala(G)1170Pro(C), revealed that ERBB____2 amplification in breast cancer is invariably monoallelic. Analysis of paired breast cancer and blood samples from informative (G1170C heterozygotic) ERBB2‐positive (n = 12) and ERBB2‐negative (n = 17) cases not only confirmed monoallelic amplification and ERBB2 transcriptional overexpression but also revealed that most low ERBB2 expressing breast cancers (12/17) exhibit unbalanced allelic transcription, showing 3‐fold to nearly 5,000‐fold preferential expression from one of two inherited alleles. To explore cis‐acting transcriptional mechanisms potentially selected during ERBB____2 amplification, levels of four different ERBB2 transcript variants (5.2, 4.7, 2.1, and 1.4 kb) were correlated with total (4.6 kb) ERBB2 mRNA levels in ERBB2‐positive (n = 14) versus ERBB2‐negative (n = 43) primary breast cancers. Relative expression of only the 2.1 kb extracellular domain‐encoding splice variant and a 4.7 kb mRNA variant that uses an alternative start site were significantly increased in association with ERBB2‐positivity, implicating altered promoter usage and selective transcript regulation within the ERBB____2 amplicon. Altogether, these findings provide new mechanistic insights into the development of ERBB2‐positive breast cancer and strong rationale for delineating candidate cis‐acting regulatory elements that may link allele‐specific ERBB2 transcription in premalignant breast epithelia with subsequent development of breast cancers bearing monoallelic ERBB____2 amplicons. © 2006 Wiley‐Liss, Inc.