Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/-mice

Karen A Dunphy,Anneke C Blackburn,Haoheng Yan,D Joseph Jerry,Lauren R O'Connell

doi:10.1186/bcr2094

Abstract

IntroductionTreatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome.MethodsMice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor incidence were examined in BALB/c-Trp53+/- mammary tissues.ResultsNuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared with placebo and age-matched virgins. This effect was sustained for at least 7 weeks after E+P treatment and did not depend on the continued presence of ovarian hormones. Hormone stimulation also enhanced apoptotic responses to ionizing radiation in BALB/c-Trp53+/- mice but these responses were intermediate compared with Trp53+/+ and Trp-/- tissues, indicating haploinsufficiency. The appearance of spontaneous mammary tumors was delayed by parity in BALB/c-Trp53+/- mice. The majority of tumors lacked estrogen receptor (ER), but ER+ tumors were observed in both nulliparous and parous mice. However, apoptotic responses to ionizing radiation and tumor incidence did not differ among outgrowths of epithelial transplants from E+P-treated donors and nulliparous donors.ConclusionTherefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.

Highlights

Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53
Nuclear accumulation of p53 and apoptotic responses were increased in the mammary epithelium from E+Ptreated and parous mice compared with placebo and agematched virgins
E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppress mammary tumorigenesis, but this effect was not retained in epithelial outgrowths

Summary

Introduction

Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. Reproductive history predicts the potential for breast cancer development. Early menarche or late menopause increases lifetime exposure to estrogen and both are associated with increased breast cancer risk [2,3]. A full-term pregnancy early in reproductive life reduces breast cancer incidence in women by up to 50% [4,5]. Pregnancy reduces the incidence of carcinogeninduced mammary tumors in rodents [6]. Treatment with estrogen and progesterone (E+P) to mimic serum levels during pregnancy is sufficient to reduce the incidence of carcinogeninduced mammary tumors in rodents [7,8,9]

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