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

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 (o1%). Systemic injections of estrogen and progesterone (E þ P) for 72 h were necessary to recover maximal expression of p21/ WAF1 following ionizing radiation (55%). The effects of E þ P on radiation-induced p21/WAF1 were p53-dependent as responses were absent in Trp53 À/À 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 þ P act directly upon the mammary gland. Treatment with E þ P was sufficient to render p53 responsive to radiation, but TGF-b-neutralizing antibodies blocked responsiveness. In the absence of E þ P, TGF-b1 alone did not alter p53 activity. These results demonstrate that estrogen and progesterone together with TGF-b signaling are necessary for maintenance of p53 activity in the mammary epithelium.

The pleiotropic roles of transforming growth factor beta in homeostasis and carcinogenesis of endocrine organs

“…It was postulated that the protective effect of hormones in mammary carcinogenesis might, in part, be related to regulation of p53 activation (Becker et al 2005). Proof of principle experiments examining p53-deficient mammary tissues demonstrated a lack of parity-induced protection, confirming the participation of p53 in hormonal-mediated chemoprevention (Medina & Kittrell 2003).…”

“…Recent analyses demonstrate a direct cross talk between TGF-b and hormones in the process of p53 activation within irradiated mammary epithelium. In ovariectomized mice, systemic injections of estrogen and progesterone were necessary to recover maximal expression of cell cycle regulators following ionizing radiation (Becker et al 2005). While ovarian steroid hormone administration augmented the p53 response to radiation (Becker et al 2005), neutralization of TGF-b blocked responsiveness (Ewan et al 2002b).…”

“…In ovariectomized mice, systemic injections of estrogen and progesterone were necessary to recover maximal expression of cell cycle regulators following ionizing radiation (Becker et al 2005). While ovarian steroid hormone administration augmented the p53 response to radiation (Becker et al 2005), neutralization of TGF-b blocked responsiveness (Ewan et al 2002b). The surprising conclusion from these experiments is that TGF-b, representing an extracellular signaling molecule, determines p53 response to DNA damage caused by radiation.…”

“…Jerry and coworkers ruled out direct DNA damage as well as direct transcriptional regulation as potential mechanisms by which these hormones regulate p53 activation (Becker et al 2005). Moreover, as TGF-b gene dose affects radiation-induced p53 phosphorylation and not total protein, it is likely that estrogen þ progesterone et al 2002b).…”

Regulation of Mammary Progenitor Cells by p53 and Parity

“…The research in our lab has shown that the p53 tumor suppressor pathway is a crucial downstream effector for this protection mechanism 5,6 . Parous mammary epithelium showed significantly higher apoptotic response to ionizing radiation (IR) which was p53-dependent 7,8 . Recent research showed p53 might also participate in the regulation of tissue-specific stem cells 9,10 .…”