Research article

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

Karen A Dunphy¹ , Anneke C Blackburn^1,2 , Haoheng Yan¹ , Lauren R O'Connell¹ and D Joseph Jerry^1,3

¹  Department of Veterinary & Animal Sciences and Molecular & Cellular Biology Program, University of Massachusetts, 300 Massachusetts Avenue, Amherst, MA 01003, USA

²  Current address: John Curtin School of Medical Research, Australian National University, Garran Road, Canberra ACT 0200, Australia

³  Pioneer Valley Life Sciences Institute, Springfield, 3601 Main Street, MA 01199, USA

author email corresponding author email

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

Published:	12 May 2008

Abstract

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. 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.

Methods

Mice 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.

Results

Nuclear 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.

Conclusion

Therefore, 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.