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Estrogen and progesterone regulate radiation-induced p53 activity in mammary epithelium through TGF-β-dependent pathways

Oncogene volume 24, pages 6345–6353 (2005)Cite this article

Abstract

DNA damage normally induces p53 activity, but responses to ionizing radiation in the mammary epithelium vary among developmental stages. The following studies examined the hormones and growth factors that regulate radiation-responsiveness of p53 in mouse mammary epithelium. Immunoreactive p21/WAF1 and TUNEL staining were used as indicators of p53 activity following exposure to ionizing radiation. In ovariectomized mice, radiation-induced accumulation of p21/WAF1 was minimal in the mammary epithelial cells (<1%). Systemic injections of estrogen and progesterone (E+P) for 72 h were necessary to recover maximal expression of p21/WAF1 following ionizing radiation (55%). The effects of E+P on radiation-induced p21/WAF1 were p53-dependent as responses were absent in Trp53−/− mice. Though hormonal treatments stimulated increases in the proportion of cycling cells (PCNA-positive), this was not directly correlated with p53 activity. Whole organ cultures were used to determine whether E+P act directly upon the mammary gland. Treatment with E+P was sufficient to render p53 responsive to radiation, but TGF-β-neutralizing antibodies blocked responsiveness. In the absence of E+P, TGF-β1 alone did not alter p53 activity. These results demonstrate that estrogen and progesterone together with TGF-β signaling are necessary for maintenance of p53 activity in the mammary epithelium.

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Acknowledgements

We thank Amy Roberts for providing p53-deficient mice for these experiments. Brooke Pazik provided technical assistance with immunohistology. We thank Michael Sutherland from the Statistical Consulting Center for his assistance. We also thank Lauren Withington, Lawrence Sandi, Kathryn Levaseure, and Jennifer Cohen, undergraduates who participated in this work. This work was supported by grants to DJJ from the National Institutes of Health (CA87531, CA095164), the Massachusetts Department of Public Health (43088PPP1017), and the Charlotte Geyer Foundation with additional support from the Cooperative State Research Extension, Education Service, US Department of Agriculture, Massachusetts Agricultural Experiment Station and Department of Veterinary and Animal Sciences under Project Nos. MAS00821 and NC-1010.

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  1. Molecular and Cellular Biology Program, University of Massachusetts, Amherst, 01003, MA, USA

    Klaus A Becker, Shaolei Lu, Karen A Dunphy, Lesley Mathews, Sallie Smith Schneider & D Joseph Jerry

  2. Department of Veterinary and Animal Sciences, Paige Laboratory, University of Massachusetts, 161 Holdsworth Way, 01003, MA, Amherst, USA

    Klaus A Becker, Shaolei Lu, Ellen S Dickinson, Karen A Dunphy & D Joseph Jerry

  3. Baystate Medical Center/UMass Biomedical Research Institute, Springfield, 01099, MA, USA

    Lesley Mathews & Sallie Smith Schneider

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  1. Klaus A Becker
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Correspondence to D Joseph Jerry.

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Becker, K., Lu, S., Dickinson, E. et al. Estrogen and progesterone regulate radiation-induced p53 activity in mammary epithelium through TGF-β-dependent pathways. Oncogene 24, 6345–6353 (2005). https://doi.org/10.1038/sj.onc.1208787

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