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 , Lauren R O'Connell and D JOSEPH Jerry

Breast Cancer Research 2008, 10:R43doi:10.1186/bcr2094


Published:	9 May 2008

Abstract (provisional)

Introduction

Treatment with estrogen and progesterone mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous estrogen and progesterone prime p53 to be more responsive to DNA damage and if these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome.

Methods

Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with estrogen and progesterone (E+P) for 14 days, 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.

Results

Nuclear accumulation of p53 and apoptotic responses were increased similarly in the mammary epithelium from E+P-treated and parous mice compared to placebo and age-matched virgins. This effect is 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 were intermediate compared to Trp53+/+ and Trp53-/- 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-positive 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.

Conclusions

Therefore, E+P and parity confer a sustained increase in p53-mediated apoptosis within the mammary epithelium and suppresses mammary tumorigenesis, but this effect was not retained in epithelial outgrowths.