A mammary-specific, long-range deletion on mouse chromosome 11 accelerates Brca1-associated mammary tumorigenesis

Aleata A. Triplett, Cristina Montagna, Kay Uwe Wagner

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

We engineered a mammary-specific knockout model for Brca1 deficiency that also lacks the majority of one chromosome 11 to determine whether tumor susceptibility loci reside on this chromosome that cooperate with the loss of Brca1 during mammary cancer formation. Brca1-deficient females that are haploinsufficient in 60 cM of chromosome 11 exhibited accelerated mammary tumorigenesis in comparison to Brca1 conditional knockout mice. On the histopathologic level, these tumors were either adenocarcinomas or benign, inflammatory lesions. Like human BRCA1-associated breast cancers, mammary carcinomas in this new mouse model were ER?-negative and of basal epithelial origin. Brca1 deficiency and haploinsufficiency in 60 cM of chromosome 11 caused widespread genome instability as determined by spectral karyotyping analysis. In addition to the verification of the long-range deletion event, the spectral karyotyping analysis revealed that the duplication of the genome and higher degree of aneuploidy occur rather late in tumor progression. Despite chromosomal rearrangements near the Trp53 locus as determined by fluorescence in situ hybridization, the Trp53 gene was transcriptionally active. The analysis of the coding sequence and expression pattern of p53 and p21 suggests that loss-of-heterozygosity of Trp53 caused by somatic mutations contributes to accelerated mammary tumorigenesis in this model.

Original languageEnglish (US)
Pages (from-to)1325-1334
Number of pages10
JournalNeoplasia
Volume10
Issue number12
DOIs
StatePublished - Dec 2008

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Chromosomes, Human, Pair 11
Carcinogenesis
Breast
Spectral Karyotyping
Breast Neoplasms
Haploinsufficiency
Neoplasms
Genomic Instability
Loss of Heterozygosity
Aneuploidy
Fluorescence In Situ Hybridization
Knockout Mice
Sequence Analysis
Adenocarcinoma
Chromosomes
Genome
Mutation
Genes

ASJC Scopus subject areas

  • Cancer Research

Cite this

A mammary-specific, long-range deletion on mouse chromosome 11 accelerates Brca1-associated mammary tumorigenesis. / Triplett, Aleata A.; Montagna, Cristina; Wagner, Kay Uwe.

In: Neoplasia, Vol. 10, No. 12, 12.2008, p. 1325-1334.

Research output: Contribution to journalArticle

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