Centrosome abnormalities, recurring deletions of chromosome 4, and genomic amplification of HER2/neu define mouse mammary gland adenocarcinomas induced by mutant HER2/neu

Abstract

The conditional expression of activated HER2/neu gene under its endogenous promoter in the mammary epithelium of the mouse results in accelerated lobular development and focal mammary tumors. Carcinogenesis, however, requires ampli®cation and considerably increased expression levels of oncogenic neu. Deducing from the multiple genetic aberrations required for human breast cancer to develop, we hypothesized that in addition to the over-expression of an activated HER2/ neu, secondary aberrations would occur. We have therefore conducted a genomic screen for chromosomal imbalances and translocations using comparative genomic hybridization and spectral karyotyping. The results reveal a moderate degree of chromosomal instability and micronuclei formation in short-term cultures established from primary tumors. Genomic instability appears to be linked to the ampli®cation of functional centrosomes, a phenomenon that we frequently observed in other tumor types. Seventy per cent of the tumors revealed genomic ampli®cation of HER2/neu, often in the form of double minute chromosomes, which correlated with recurring loss of mouse chromosome 4D-E, a region that is orthologous to distal human chromosome 1p. It is likely that this region contains putative tumor suppressor genes whose inactivation is required for tumor formation in this model of human breast cancer.

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

“…By CGH we observed an ANCA of 8.1 for the Brca1-deficient mammary tumors. This number is higher than in murine tumors induced by overexpression of an oncogene, such as in MMTV-c-myc (ANCA=5.5) or Erbb2 (ANCA-2.7) transgenics Montagna et al, 2002). Conditional knockout of the Brca1 tumor suppressor gene may more closely model familial breast cancer as the second allele is only mutated as the mice reach maturity (Xu et al, 1999a).…”

Loss of the 14-3-3σ Tumor Suppressor Is a Critical Event in ErbB2-Mediated Tumor Progression

“…Previous studies with the ErbB2 KI model indicated that one important genomic alteration involved in tumor progression is the loss of a chromosomal region spanning the 14-3-3σ locus that is correlated with loss of 14-3-3σ expression (15,17). To directly address whether loss of 14-3-3σ is a critical event in ErbB2-driven tumor progression, we intercrossed mice bearing the conditional 14-3-3σ allele to ErbB2 KI mice to generate cohorts of ErbB2 KI female mice with one or two conditional 14-3-3σ alleles.…”

“…S1C). Given that the average tumor chromosome 4 (15). Refined CGH/BAC analyses revealed that in addition to the erbB2 amplicon, there was a frequent loss of a chromosomal region spanning the 14-3-3σ tumor suppressor locus (16,17).…”

Oncogenes and Tumor Suppressor Genes

“…Tumor progression in these strains is associated with a dramatic elevation in the levels of both ErbB2 mRNA and protein. Remarkably, the elevated expression of ErbB2 also correlates with selective genomic amplification of the activated ErbB2 allele (Andrechek et al 2000;Montagna et al 2002;Hodgson et al 2005). Thus, as in human breast cancers, amplification of ErbB2 appears to be a critical event in mammary tumor progression in this mouse model.…”

“…Tumorigenesis in the ErbB2 KI model is also associated with a number of other alterations, including centrosome abnormalities and recurrent deletions of chromosome 4 (Montagna et al 2002). Further refined mapping of chromosome 4 region has revealed that these tumors have frequently loss of expression of the tumor suppressor 14-3-3s (Hodgson et al 2005).…”