INVESTIGATING MECHANISMS OF RACIALLY DISPARATE PREGNANCY PROTECTION IN A HUMANIZED MOUSE MODEL

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 498-514-Female Reproductive Endocrinology
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-500
Thomas Berton*1, Isabel Lambertz2, Ramesh Gunaratna1, Claudio Conti2 and Robin S L Fuchs-Young3
1Texas A&M Health Science Center, 2Texas A&M Health Science Center, TX, 3Dept of Molecular & Cellular Medicine, College Station, TX
African American (AA) women have a greater tendency to develop pre-menopausal breast cancer and also have a greater likelihood of developing aggressive, basal-like and TNT subtypes that have poorer outcomes.  Additionally, AA women frequently do not benefit from the effects of early pregnancy that epidemiological studies show confers a modest, but significant, overall lifetime protection against breast cancer in White women. The molecular basis for these persistent outcome and protection disparities is likely multifactorial, but remains unresolved. Since animal studies show that p53 is a critical mediator of pregnancy protection in vivo, we used a humanized mouse model harboring a racially disparate p53 polymorphism at codon 72 (p53R72P) to investigate this effect.  The frequency of the R allele, which has been shown to be a more potent inhibitor of oncogenic transformation due to increased induction of apoptosis, is substantially lower in AA women (33.3%) than in White women (76.7%). To study the potential contributions of p53 polymorphisms to differential pregnancy protection, we treated knock-in mice with estrogen and progesterone (E2+P) for 21 days, which recapitulates the hormonal milieu of pregnancy. Following hormone treatment, p53 gene expression was similar in mammary glands from p53mouseWT/mouseWT, p53P/P and p53R/R mice, however, p53 protein expression was significantly higher in the glands from p53R/R mice compared to those from the p53P/P and p53mWT/mWT genotypes. To determine if the hormonally-induced expression of p53 in the mammary gland afforded protection against DNA damage, mice were exposed to ionizing radiation (IR).  In response to IR challenge, p53 expression and p53(S15) phosphorylation were higher in the glands from p53R/R mice, compared to the p53P/P mice.  Importantly, the p53R/R mice were also afforded greater protection against IR-induced DNA damage, as glands from these mice showed significantly higher levels of apoptosis, as measured by activated caspase-3 immunohistochemistry. These data indicate that mammary glands from mice with the racially disproportionate P/P genotype have reduced levels of p53 expression, activation and subsequent apoptosis following E2+P treatment and IR challenge, suggesting that this polymorphism contributes to reduced pregnancy protection in AA women, and may also affect the development of more aggressive, early onset phenotypes with poorer prognosis.

Nothing to Disclose: TB, IL, RG, CC, RSLF

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH grant:   R01MD006228 to RFY