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Brca1 inactivation induces p27Kip1-dependent cell cycle arrest and delayed development in the mouse mammary gland

Oncogene volume 23, pages 6136–6145 (2004)Cite this article

Abstract

One common characteristic of breast cancers arising in carriers of the predisposition gene BRCA1 is a loss of expression of the CDK inhibitor p27Kip1 (p27), suggesting that p27 interacts epistatically with BRCA1. To investigate this relationship, we examined expression of p27 in mice expressing a dominant negative allele of Brca1 (MMTV-trBr) in the mammary gland. While these mice rarely develop tumors, they showed a 50% increase in p27 protein and a delay in mammary gland development associated with reduced proliferation. In contrast, on a p27 heterozygote background, MMTV-trBrca1 mice showed an increase in S phase cells, and normal mammary development. p27 was the only protein in the cyclin–cyclin-dependent kinase network to show altered expression, suggesting that it may be a central mediator of cell cycle arrest in response to loss of function of BRCA1. Furthermore, in human mammary epithelial MCF7 cells expressing BRCA1-specific RNAi and in the BRCA1-deficient human tumor cell line HCC1937, p27 is elevated at the mRNA level compared to cells expressing wild-type BRCA1. We hypothesize that disruption of BRCA1 induces an increase in p27 that inhibits proliferation. Accordingly, reduction in p27 expression leads to enhancement of cellular proliferation in the absence of BRCA1.

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Abbreviations

CDK:

cyclin-dependent kinase

MMTV-LTR:

mouse mammary tumor virus-long terminal repeat

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

dpc:

days post coitus

E+P:

estradiol and progesterone

QRT-PCR:

quantitative real-time PCR

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Acknowledgements

We acknowledge Ellen Solomon and James Roberts for providing breeding pairs of MMTV-trBrca1 and p27-deficient mice, respectively, Beric Henderson for assistance with the HCC1937 cell line, Jacob Jackson for producing the LXSN-RecN amphotrophic retrovirus, and Reuven Agami for the pSuper plasmid. We thank Max Walker for animal husbandry, Sandra Grimm for assistance with mouse hormone dosages, Brenda Aisbett for assistance with histology, Andrew Fryga and Ralph Rossi for flow cytometry support, and Paul Waring for pathology. We also thank Nicole Lundie, Liz Musgrove, and Doris Germain for critical reading of the manuscript. This work was supported by grants from the National Health and Medical Research Council of Australia and the Cancer Council of Victoria, Australia. AD is the recipient of a Postgraduate Award from the Cancer Council of Victoria, Australia.

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Authors and Affiliations

  1. Molecular Oncology Laboratory, Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, 3002, Australia

    Andrew J Deans & Grant A McArthur

  2. Department of Medicine (St Vincent's), The University of Melbourne, Parkville, 3052, Australia

    Andrew J Deans & Grant A McArthur

  3. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, 3052, Australia

    Kaylene J Simpson

  4. Department of Pathology, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, 3002, Australia

    Melanie K Trivett

  5. Department of Biochemistry and Molecular Biology, University of Queensland, Brisbane, 4072, Australia

    Melissa A Brown

  6. Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, St Andrew's Place, East Melbourne, 3002, Australia

    Grant A McArthur

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Correspondence to Grant A McArthur.

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Deans, A., Simpson, K., Trivett, M. et al. Brca1 inactivation induces p27Kip1-dependent cell cycle arrest and delayed development in the mouse mammary gland. Oncogene 23, 6136–6145 (2004). https://doi.org/10.1038/sj.onc.1207805

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