Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer

Zoë Weaver, Cristina Montagna, Xiaoling Xu, Tamara Howard, Massimo Gadina, Steven G. Brodie, Chu Xia Deng, Thomas Ried

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

BRCA1 mutation carriers have an increased susceptibility to breast and ovarian cancer. Excision of exon 11 of Brca1 in the mouse, using a conditional knockout (Cre-loxP) approach, results in mammary tumor formation after long latency. To characterize the genomic instability observed in these tumors, to establish a comparative map of chromosomal imbalances and to contribute to the validation of this mouse model of breast cancer, we have characterized chromosomal imbalances and aberrations using comparative genomic hybridization (CGH), and spectral karyotyping (SKY). We found that all tumors exhibit chromosome instability as evidenced by structural chromosomal aberrations and aneuploidy, yet they display a pattern of chromosomal gain and loss that is similar to the pattern in human breast carcinomas. Of note, nine of 15 tumors exhibited a gain of distal chromosome 11, a region that is orthologous to human chromosome 17q11-qter, the mapping position of Erbb2. However, our analysis suggests that genes distal to Erbb2 are the main targets of amplification. Four of the tumors also exhibited a copy number loss of proximal chromosome 11 (11A-B), a region orthologous to human 17p. In eight of the tumors we observed whole or partial gain of chromosome 15 centering on 15D2-D3 (orthologous to human chromosome 8q24), the map location of the c-Myc gene, and six of the tumors exhibited copy number loss of whole or partial chromosome 14, including 14D3, the map location of Rb1. We conclude that despite the tremendous shuffling of chromosomes during the course of mammalian evolution, the pattern of genomic imbalances is conserved between BRCA1-associated mammary gland tumors in mice and humans. Western blot analysis showed that while p53 is absent or mutated in some tumors, at least two tumors revealed wild-type protein, suggesting that other genetic events may lead to tumorigenesis. Similar to BRCA1-deficient mouse embryonic fibroblasts, the tumor cells contained supernumerary functional centrosomes with intact centrioles whose presence results in multipolar mitoses and aneuploidy.

Original languageEnglish (US)
Pages (from-to)5097-5107
Number of pages11
JournalOncogene
Volume21
Issue number33
DOIs
StatePublished - Aug 1 2002
Externally publishedYes

Fingerprint

Centrosome
Genomic Instability
Breast Neoplasms
Neoplasms
Chromosomes, Human, Pair 11
Human Chromosomes
Aneuploidy
Chromosome Aberrations
Spectral Karyotyping
Centrioles
Chromosomes, Human, Pair 15
Chromosomes, Human, Pair 14
Chromosomal Instability
myc Genes
Comparative Genomic Hybridization
Human Mammary Glands
Mitosis
Ovarian Neoplasms
Exons
Carcinogenesis

Keywords

  • Brca1
  • Centrosome
  • Genomic imbalances
  • Mouse models
  • SKY

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer. / Weaver, Zoë; Montagna, Cristina; Xu, Xiaoling; Howard, Tamara; Gadina, Massimo; Brodie, Steven G.; Deng, Chu Xia; Ried, Thomas.

In: Oncogene, Vol. 21, No. 33, 01.08.2002, p. 5097-5107.

Research output: Contribution to journalArticle

Weaver, Zoë ; Montagna, Cristina ; Xu, Xiaoling ; Howard, Tamara ; Gadina, Massimo ; Brodie, Steven G. ; Deng, Chu Xia ; Ried, Thomas. / Mammary tumors in mice conditionally mutant for Brca1 exhibit gross genomic instability and centrosome amplification yet display a recurring distribution of genomic imbalances that is similar to human breast cancer. In: Oncogene. 2002 ; Vol. 21, No. 33. pp. 5097-5107.
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abstract = "BRCA1 mutation carriers have an increased susceptibility to breast and ovarian cancer. Excision of exon 11 of Brca1 in the mouse, using a conditional knockout (Cre-loxP) approach, results in mammary tumor formation after long latency. To characterize the genomic instability observed in these tumors, to establish a comparative map of chromosomal imbalances and to contribute to the validation of this mouse model of breast cancer, we have characterized chromosomal imbalances and aberrations using comparative genomic hybridization (CGH), and spectral karyotyping (SKY). We found that all tumors exhibit chromosome instability as evidenced by structural chromosomal aberrations and aneuploidy, yet they display a pattern of chromosomal gain and loss that is similar to the pattern in human breast carcinomas. Of note, nine of 15 tumors exhibited a gain of distal chromosome 11, a region that is orthologous to human chromosome 17q11-qter, the mapping position of Erbb2. However, our analysis suggests that genes distal to Erbb2 are the main targets of amplification. Four of the tumors also exhibited a copy number loss of proximal chromosome 11 (11A-B), a region orthologous to human 17p. In eight of the tumors we observed whole or partial gain of chromosome 15 centering on 15D2-D3 (orthologous to human chromosome 8q24), the map location of the c-Myc gene, and six of the tumors exhibited copy number loss of whole or partial chromosome 14, including 14D3, the map location of Rb1. We conclude that despite the tremendous shuffling of chromosomes during the course of mammalian evolution, the pattern of genomic imbalances is conserved between BRCA1-associated mammary gland tumors in mice and humans. Western blot analysis showed that while p53 is absent or mutated in some tumors, at least two tumors revealed wild-type protein, suggesting that other genetic events may lead to tumorigenesis. Similar to BRCA1-deficient mouse embryonic fibroblasts, the tumor cells contained supernumerary functional centrosomes with intact centrioles whose presence results in multipolar mitoses and aneuploidy.",
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AU - Xu, Xiaoling

AU - Howard, Tamara

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AU - Brodie, Steven G.

AU - Deng, Chu Xia

AU - Ried, Thomas

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