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Expression of the NF-κB-responsive gene BTG2 is aberrantly regulated in breast cancer

Oncogene volume 23, pages 8310–8319 (2004)Cite this article

Abstract

BTG2, a p53-inducible antiproliferative gene, is stimulated in breast cancer cells by activation of nuclear factor kappa B (NF-κB). In rat mammary glands, BTG2 is expressed in epithelial cells and levels decreased during pregnancy and lactation but recovered during involution. Estrogen and progestin suppress BTG2 expression, suggesting that these steroids, which stimulate proliferation and lobuloalveolar development of mammary epithelial cells, may downregulate BTG2 in the mammary gland during pregnancy. Consistent with the report that BTG2 inhibits cyclin D1 expression, suppression of BTG2 mRNA in the mammary gland during gestation, and by estrogen and progestin, correlated with stimulation of cyclin D1. Ectopic expression of BTG2 inhibited breast cancer cell growth by arresting cells in the G1 phase, an effect reversed by cyclin D1. BTG2 expression was very low or undetectable in human breast cancer cell lines compared with nontumorigenic mammary epithelial cells, and nuclear expression of BTG2 was absent in 65% of human breast tumors compared with adjacent matched normal glands. Spontaneous mammary tumors arising in a mouse model with targeted expression of the early region of the SV40 large tumor Ag demonstrated loss of BTG2 protein very early during the tumorigenic process. Thus deregulation of BTG2 may be an important step in the development of mammary tumors.

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Acknowledgements

We thank Drs Emmett Schmidt, Toshi Shioda, Paul Harkin, Leif Ellisen and Jose Teixeira for critically reading this manuscript. We thank Drs Donahoe and MacLaughlin for providing the MIS used in these experiments. We thank Dr Clayton Naeve, Director of the Hartwell Center for Bioinformatics and Biotechnology at St Jude Children's Research Hospital for DNA microarray analysis. This work was supported by the Department of Defense Breast Cancer Research Grant DAMD17-03-1-0407 (to VG), NIH CA84441 (to PDW) and Department of Defense grant PC030351 (to PDW), and by the Breast Cancer Research Grant from the Massachusetts Department of Public Health, the Avon Breast Cancer Pilot Project Grant, the Claflin Distinguished Scholar Award, partial support from the Dana-Farber Harvard Breast Cancer SPORE and from NIH/NCI grant CA89138 (to S.M.).

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Authors and Affiliations

  1. Department of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, 02114, MA, USA

    Hirofumi Kawakubo, Jennifer L Carey, Vandana Gupta & Shyamala Maheswaran

  2. Department of Pathology, Massachusetts General Hospital, Boston, 02114, MA, USA

    Elena Brachtel

  3. Laboratory of Cell Regulation and Carcinogenesis, NIH, Bethesda, 20892, MD, USA

    Jeffrey E Green

  4. Department of Urology, NYU Medical Center, New York, 10016, NY, USA

    Paul D Walden

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  1. Hirofumi Kawakubo
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  2. Jennifer L Carey
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  4. Vandana Gupta
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  7. Shyamala Maheswaran
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Correspondence to Shyamala Maheswaran.

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Kawakubo, H., Carey, J., Brachtel, E. et al. Expression of the NF-κB-responsive gene BTG2 is aberrantly regulated in breast cancer. Oncogene 23, 8310–8319 (2004). https://doi.org/10.1038/sj.onc.1208008

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