Abstract LB-164: The association between p53, MDM2, and MDM2 isoform C protein expression and survival in a multiethnic population of breast cancer patients

Abstract

Abstract Breast cancer is the most common cancer among women in the United States. Despite improvements in survival rates, the disease remains the second leading cause of cancer death for women in the U.S. Breast cancer incidence and survival dramatically vary by race and ethnicity. These disparities may be attributed to racial/ethnic differences in the factors influencing breast cancer development and progression. These include factors such as personal (eg. body size and reproductive history), clinical (eg. stage, grade, histology), treatment course, and genetic susceptibility. Inactivation of the tumor suppressing, p53 pathway is a common event in breast cancer. Depending on the molecular subtype, p53 mutation is observed in 12-84% of breast cancers and is correlated with poor clinical outcome. In addition to p53 mutation events, p53 pathway inactivation in tumors can also result from an increase in the levels of MDM2, an ubiquitin ligase that functions as a negative regulator of p53. The mdm2 gene produces at least 40 differentially spliced transcripts. The MDM2 isoforms A, B, and C have been observed to be frequently overexpressed in many tumor types and correlated with poor prognosis, however, the underlying mechanism is poorly understood. To examine the protein expression profiles for p53, MDM2, and MDM2 isoform C (MDM2-C) in breast cancer from a multiethnic population, we conducted immunohistochemical (IHC) analyses utilizing commercially available antibodies to p53 and MDM2, and a newly developed monoclonal antibody specific for MDM2-C (Okoro DR et al. 2013. PLoS ONE) on a total of 791 invasive breast tumors included in a clinically-annotated population-based tissue microarray (TMA). Based on Cox proportional hazards regression analysis and adjusting for age, stage, and estrogen and progesterone receptor status, we did not observe significant associations between expression of p53, MDM2, or MDM2-C and mortality across all cases. However when we examined associations within major racial/ethnic groups included in our TMA (Caucasian, Japanese, and Native Hawaiian), we observed a significant positive association of p53 expression (HR=1.63, 95% CI: 1.02-2.59) and a marginally significant association of MDM2-C (HR=1.69, 95% CI: 0.94-3.01) with all-cause mortality for Japanese women. We also observed associations between MDM2-C expression and all-cause and breast cancer-specific mortality for Caucasian women (HR=0.60, 95% CI: 0.33-1.08 and HR=0.28, 95% CI: 0.12-0.67, respectively). However, in contrast to Japanese women, expression of MDM2-C was associated with lower risk of mortality for Caucasian women. No significant associations for Native Hawaiian women were observed. Recent reports indicate that the functional effects of MDM2 isoforms (A, B, and C) are dependent on the presence of wild-type or mutant p53, and our preliminary results suggest that the association between breast cancer outcome and MDM2-C expression is context dependent on p53 status. Citation Format: Lenora W. Loo, Brenda Y. Hernandez, Yurii Shvetsov, Danielle Okoro, Chong Gao, Jill Bargonetti. The association between p53, MDM2, and MDM2 isoform C protein expression and survival in a multiethnic population of breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-164. doi:10.1158/1538-7445.AM2017-LB-164