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Haploid loss of Ki-ras delays mammary tumor progression in C3 (1)/SV40 Tag transgenic mice

Abstract

We have previously demonstrated that amplification and overexpression of the Ki-ras gene is associated with mammary tumor progression in C3(1)/SV40Tag transgenic mice (Liu et al., 1998). To further evaluate the functional significance of the Ki-ras proto-oncogene in mammary cancer development, in vivo studies were conducted to examine the effect of Ki-ras gene dosage on tumor progression. The lack of one normal Ki-ras allele C3(1)/SV40Tag transgenic mice resulted in significantly delayed mammary intraepithelial neoplasia (MIN) formation as well as in a decreased number of mammary gland carcinomas. However, despite the retardation of tumor development by reduced Ki-ras gene dosage, overall survival was only modestly affected. This appears to be due to several factors including significant mammary tumor growth associated with Ki-ras gene amplification and over-expression that occurs during the advanced stage of oncogenesis in mice carrying either one or two normal Ki-ras alleles. The retardation of tumor progression due to the haploid loss of Ki-ras did not appear to be related to accelerated apoptosis, or a reduced rate of cell proliferation at the tumor stages examined. These data strongly suggest that the gene dosage of Ki-ras affects tumor promotion at an early stage of mammary tumor progression in this SV40 Tag-induced model of mammary oncogenesis.

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Abbreviations

Ab:

antibody

AH:

atypical hyperplasia

BrdU:

5-bromo-2′-deoxyuridine

ISH:

in situ hybridization

NAH:

nodular atypical hyperplasia

PCR:

polymerase chain reaction

SV40Tag:

simian virus 40 large T antigen

TUNEL:

terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling.

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Acknowledgements

The authors are grateful to Lisa Birely for excellent technical assistance with animal care, Tyler Jacks for kindly providing the S-9-2 plasmid containing the ki-ras genomic fragment and providing mice carrying the ki-ras mutant allele, and Kartiki Desai for critical review of the manuscript.

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Liu, ML., Shibata, MA., Von Lintig, F. et al. Haploid loss of Ki-ras delays mammary tumor progression in C3 (1)/SV40 Tag transgenic mice. Oncogene 20, 2044–2049 (2001). https://doi.org/10.1038/sj.onc.1204280

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Keywords

  • Ki-ras
  • mammary gland tumor
  • transgenic mice

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