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MDM2, MDM2-C, and mutant p53 expression influence breast cancer survival in a multiethnic population

Abstract

Purpose

The purpose of the study was to examine the association between expression of mutant p53 (mtp53), full-length MDM2 (MDM2), and MDM2 isoform C (MDM2-C) and survival in multiethnic breast cancer patients.

Methods

A total of 787 invasive breast tumors included in a clinically annotated multiethnic population-based tissue microarray (TMA) were screened utilizing commercially available antibodies to p53 and MDM2, and a newly developed monoclonal antibody recognizing MDM2-C.

Results

Mutant p53 (mtp53) was more common in younger (< 50 years) breast cancer patients. Among the 787 cases included in the study, mtp53, MDM2, and MDM2-C expression were not significantly associated with risk of overall or breast cancer-specific mortality. However when associations within individual racial/ethnic groups (White, Japanese, and Native Hawaiian) were examined, expression of MDM2-C was found to be associated with lower risk of breast cancer-specific mortality exclusively for White patients HR 0.32, 95% CI 0.15–0.69 and mtp53 expression was associated with higher overall mortality in Japanese patients (HR 1.63, 95% CI 1.02–2.59). Also, Japanese patients positive for the joint expression of MDM2-C and mtp53 had a greater than twofold risk of overall mortality (HR 2.15, 95% CI 1.04–4.48); and White patients with positive MDM2-C and wild-type p53 expression (HR 0.28, 95% CI 0.08–0.96) were at lower risk of mortality when compared to patients with negative MDM2-C and wild-type p53 expression in their respective racial/ethnic group.

Conclusion

Racial/ethnic differences in expression profiles of mtp53, MDM2, and MDM2-C and associations with breast cancer-specific and overall mortality. MDM2-C may have a positive or negative role in breast tumorigenesis depending on mtp53 expression.

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Acknowledgements

The authors would like to acknowledge the Memorial Sloan Kettering Cancer Center Antibody and Bioresource Core Facility for excellent assistance with the generation of hybridomas, the Hawaii Tumor Registry, Residual Tissue Repository of the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End-Results (SEER) program, and the University of Hawaii Cancer Center’s Biostatistics Shared Resource and Pathology Shared Resource for their contribution to this project.

Funding

This study was funded by the National Institute on Minority Health and Health Disparities (U54MD008149-SGP14-183; MD007599), NCI (R21CA176555-01A1; 3P30CA071789-12S7), Hawaii Community Foundation (16ADVC-78885), and the Breast Cancer Research Foundation.

Author information

Correspondence to Lenora W. M. Loo.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest to disclose.

Ethical approval

This study has received ethical approval by the University of Hawaii Committee on Human Studies. This study was a retrospective study, with all subjects having been de-identified, and no formal consent was required. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For the generation of the monoclonal antibodies, all applicable international, national, and institutional guidelines for the care and use of animals were followed.

Electronic supplementary material

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Supplemental Figure 1. Breast tumor tissue expression of MDM2, MDM2-C and p53 proteins and 10 year overall survival by race/ethnicity. Kaplan-Meier curves and log-rank tests were used to compare survival distribution by protein expression of MDM2, MDM2-C and p53 for all and individually racial/ethnic groups (i.e. Native Hawaiians, Japanese, and Whites) without adjustment and up to 120 months (10 years) of follow-up (PPTX 244 KB)

Supplemental Figure 2. Breast tumor tissue expression of MDM2, MDM2-C and p53 proteins and 10 year overall survival by estrogen receptor status. Kaplan-Meier curves and log-rank tests were used to compare survival distribution by protein expression of MDM2, MDM2-C and p53 by ER-status, without adjustment and up to 120 months (10 years) of follow-up (PPTX 144 KB)

Supplementary material 3 (DOC 50 KB)

Supplementary material 4 (XLS 41 KB)

Supplementary material 5 (DOC 45 KB)

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Loo, L.W.M., Gao, C., Shvetsov, Y.B. et al. MDM2, MDM2-C, and mutant p53 expression influence breast cancer survival in a multiethnic population. Breast Cancer Res Treat 174, 257–269 (2019). https://doi.org/10.1007/s10549-018-5065-7

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Keywords

  • Breast cancer
  • MDM2
  • MDM2-C
  • P53
  • Multiethnic
  • Survival