 Research articleEstrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- miceKaren A Dunphy1 , Anneke C Blackburn1,2 , Haoheng Yan1 , Lauren R O'Connell1 and D Joseph Jerry1,3  1Department of Veterinary & Animal Sciences and Molecular & Cellular Biology Program, University of Massachusetts, 300 Massachusetts Avenue, Amherst, MA 01003, USA 2Current address: John Curtin School of Medical Research, Australian National University, Garran Road, Canberra ACT 0200, Australia 3Pioneer 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 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. |