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Altered promoter usage characterizes monoallelic transcription arising with ERBB2 amplification in human breast cancers
Author(s) -
Benz Christopher C.,
Fedele Vita,
Xu Fan,
Ylstra Bauke,
Ginzinger David,
Yu Mamie,
Moore Dan,
Hall Rayna Kneuper,
Wolff Daynna J.,
Disis Mary L.,
EppenbergerCastori Serenella,
Eppenberger Urs,
Schittulli Francesco,
Tommasi Stefania,
Paradiso Angelo,
Scott Gary K.,
Albertson Donna G.
Publication year - 2006
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20364
Subject(s) - biology , breast cancer , erbb , allele , amplicon , genotyping , cancer research , gene , single nucleotide polymorphism , genetics , genotype , microbiology and biotechnology , cancer , polymerase chain reaction
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.