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

TitleEstrogen and progesterone regulate radiation-induced p53 activity in mammary epithelium through TGF-beta-dependent pathways.
Publication TypeJournal Article
Year of Publication2005
AuthorsBecker KA, Lu S, Dickinson ES, Dunphy KA, Mathews L, Schneider SS, Jerry JD
JournalOncogene
Volume24
Issue42
Pagination6345-53
Date Published2005 Sep 22
AbstractDNA 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-beta-neutralizing antibodies blocked responsiveness. In the absence of E+P, TGF-beta1 alone did not alter p53 activity. These results demonstrate that estrogen and progesterone together with TGF-beta signaling are necessary for maintenance of p53 activity in the mammary epithelium.
Alternate JournalOncogene