Altered promoter usage characterizes monoallelic transcription arising with ERBB2 amplification in human breast cancers

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 Albertson

Research output: Contribution to journalArticle

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 ERBB2 single nucleotide polymorphism Ala(G)1170Pro(C), revealed that ERBB2 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 ERBB2 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 ERBB2 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 ERBB2 amplicons.

Original languageEnglish (US)
Pages (from-to)983-994
Number of pages12
JournalGenes Chromosomes and Cancer
Volume45
Issue number11
DOIs
StatePublished - Nov 2006

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Breast Neoplasms
Alleles
Messenger RNA
Single Nucleotide Polymorphism
Breast
Epithelium
Population
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

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Altered promoter usage characterizes monoallelic transcription arising with ERBB2 amplification in human breast cancers. / Benz, Christopher C.; Fedele, Vita; Xu, Fan; Ylstra, Bauke; Ginzinger, David; Yu, Mamie; Moore, Dan; Hall, Rayna Kneuper; Wolff, Daynna J.; Disis, Mary L.; Eppenberger-Castori, Serenella; Eppenberger, Urs; Schittulli, Francesco; Tommasi, Stefania; Paradiso, Angelo; Scott, Gary K.; Albertson, Donna.

In: Genes Chromosomes and Cancer, Vol. 45, No. 11, 11.2006, p. 983-994.

Research output: Contribution to journalArticle

Benz, CC, Fedele, V, Xu, F, Ylstra, B, Ginzinger, D, Yu, M, Moore, D, Hall, RK, Wolff, DJ, Disis, ML, Eppenberger-Castori, S, Eppenberger, U, Schittulli, F, Tommasi, S, Paradiso, A, Scott, GK & Albertson, D 2006, 'Altered promoter usage characterizes monoallelic transcription arising with ERBB2 amplification in human breast cancers', Genes Chromosomes and Cancer, vol. 45, no. 11, pp. 983-994. https://doi.org/10.1002/gcc.20364
Benz, Christopher C. ; Fedele, Vita ; Xu, Fan ; Ylstra, Bauke ; Ginzinger, David ; Yu, Mamie ; Moore, Dan ; Hall, Rayna Kneuper ; Wolff, Daynna J. ; Disis, Mary L. ; Eppenberger-Castori, Serenella ; Eppenberger, Urs ; Schittulli, Francesco ; Tommasi, Stefania ; Paradiso, Angelo ; Scott, Gary K. ; Albertson, Donna. / Altered promoter usage characterizes monoallelic transcription arising with ERBB2 amplification in human breast cancers. In: Genes Chromosomes and Cancer. 2006 ; Vol. 45, No. 11. pp. 983-994.
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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 ERBB2 single nucleotide polymorphism Ala(G)1170Pro(C), revealed that ERBB2 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 ERBB2 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 ERBB2 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 ERBB2 amplicons.",
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AU - Ginzinger, David

AU - Yu, Mamie

AU - Moore, Dan

AU - Hall, Rayna Kneuper

AU - Wolff, Daynna J.

AU - Disis, Mary L.

AU - Eppenberger-Castori, Serenella

AU - Eppenberger, Urs

AU - Schittulli, Francesco

AU - Tommasi, Stefania

AU - Paradiso, Angelo

AU - Scott, Gary K.

AU - Albertson, Donna

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N2 - 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 ERBB2 single nucleotide polymorphism Ala(G)1170Pro(C), revealed that ERBB2 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 ERBB2 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 ERBB2 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 ERBB2 amplicons.

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