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Deletion of Tip30 leads to rapid immortalization of murine mammary epithelial cells and ductal hyperplasia in the mammary gland

Oncogene volume 26, pages 7423–7431 (2007)Cite this article

Abstract

Transformation of mammary epithelial cells (MECs) from the normal to the neoplastic stage requires the dysregulation of tumor suppressor genes and proto-oncogenes. Tip30 is a tumor suppressor that can inhibit estrogen receptor-mediated transcription in MECs, but its role in MEC proliferation remains unknown. Here, we show that deleting the Tip30 gene leads to ductal hyperplasia in mouse mammary glands early in life and extensive mammary hyperplasia with age. Tip30−/− mammary glands transplanted into wild-type mammary fat pads also display mammary trees with extensive ductal hyperplasia. Strikingly, Tip30 deletion promotes proliferation of primary MECs and results in rapid immortalization of MECs in vitro relative to wild-type cells. Gene array analysis identified significant increases in the expression of mammary epithelial growth factors Wisp2 and Igf-1 in Tip30−/− cells. Knockdown of either Wisp2 or Igf-1 using short interfering RNA dramatically inhibited proliferation of Tip30−/− cells. Together, these results suggest that Tip30 is an intrinsic and negative regulator of MEC proliferation partly through the inhibition of Wisp2 and Igf-1 expression, and its absence in the mammary gland may predispose MECs to neoplastic transformation.

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Acknowledgements

We thank Drs C-Wu and Y Qin for their histopathological expertise, J Wahl for providing E-cadherin antibodies. We also thank C Eischen for her generous help and advice and S Haslam for critical reading of the paper. This work was supported by grants from National Institute of Health Grants DK066110-01 and American Cancer Society Grant RSG0216501GMC to HX. WT was supported by Department of Defense postdoctoral traineeship award, DAMD17-001-0361. JP was supported by an NIH graduate student fellowship.

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Authors and Affiliations

  1. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA

    J Pecha, C Jiang, W Tang, K Bruck & K-U Wagner

  2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA

    J Pecha & K-U Wagner

  3. Department of Physiology and Pathology, Michigan State University, East Lansing, MI, USA

    D Ankrapp, I Hoshino & H Xiao

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  1. J Pecha
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  2. D Ankrapp
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  3. C Jiang
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  6. K Bruck
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  8. H Xiao
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Correspondence to H Xiao.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Pecha, J., Ankrapp, D., Jiang, C. et al. Deletion of Tip30 leads to rapid immortalization of murine mammary epithelial cells and ductal hyperplasia in the mammary gland. Oncogene 26, 7423–7431 (2007). https://doi.org/10.1038/sj.onc.1210548

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