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

Oncogene volume 20, pages 2044–2049 (2001)Cite this article

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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Author notes

  1. Min-Ling Liu

    Present address: Department of Pathology, Georgetown University Medical Center, Washington, DC, USA

  2. Masa-Aki Shibata

    Present address: Department of Anatomy and Biology, Osaka Medical College, Osaka, 569-8686, Takatsuki, Japan

  3. Min-Ling Liu and Masa-Aki Shibata: M-L Liu and M-A Shibata contributed equally to this work

Authors and Affiliations

  1. Division of Basic Sciences, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institute of Health, Bethesda, 20892, Maryland, MD, USA

    Min-Ling Liu, Masa-Aki Shibata, Weili Wang & Jeffrey E Green

  2. Department of Medicine, University of California San Diego, La Jolla, California, CA, USA

    Friederike C Von Lintig, Stijn Cassenaer & Gerry R Boss

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  1. Min-Ling Liu
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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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