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Breast Cancer Research and Treatment

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01-02-2019 | Epidemiology

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

Authors: Lenora W. M. Loo, Chong Gao, Yurii B. Shvetsov, Danielle R. Okoro, Brenda Y. Hernandez, Jill Bargonetti

Published in: Breast Cancer Research and Treatment | Issue 1/2019

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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American Cancer Society (2018) Cancer Facts & Figs. 2018

DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A (2017) Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 67(6):439–448. https://doi.org/10.3322/caac.21412 CrossRefPubMed

Gomez SL, Noone AM, Lichtensztajn DY, Scoppa S, Gibson JT, Liu L, Morris C, Kwong S, Fish K, Wilkens LR, Goodman MT, Deapen D, Miller BA (2013) Cancer incidence trends among Asian American populations in the United States, 1990–2008. J Natl Cancer Inst 105(15):1096–1110. https://doi.org/10.1093/jnci/djt157 CrossRefPubMedPubMedCentral

Liu L, Noone AM, Gomez SL, Scoppa S, Gibson JT, Lichtensztajn D, Fish K, Wilkens LR, Goodman MT, Morris C, Kwong S, Deapen D, Miller BA (2013) Cancer incidence trends among Native Hawaiians and other Pacific Islanders in the United States, 1990–2008. J Natl Cancer Inst 105(15):1086–1095. https://doi.org/10.1093/jnci/djt156 CrossRefPubMedPubMedCentral

Liu L, Zhang J, Wu AH, Pike MC, Deapen D (2011) Invasive breast cancer incidence trends by detailed race/ethnicity and age. Int J Cancer. https://doi.org/10.1002/ijc.26004 CrossRefPubMedPubMedCentral

Miller B, Chu K, Hankey B, Ries L (2008) Cancer incidence and mortality patterns among specific Asian and Pacific Islander populations in the U.S. Cancer Causes Control 19(3):227–256CrossRefPubMed

Ooi SL, Martinez ME, Li CI (2011) Disparities in breast cancer characteristics and outcomes by race/ethnicity. Breast Cancer Res Treat 127(3):729–738. https://doi.org/10.1007/s10549-010-1191-6 CrossRefPubMed

Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70. https://doi.org/10.1038/nature11412 CrossRef

Kubbutat MH, Jones SN, Vousden KH (1997) Regulation of p53 stability by Mdm2. Nature 387(6630):299–303. https://doi.org/10.1038/387299a0 CrossRefPubMed

10.

Li M, Brooks CL, Wu-Baer F, Chen D, Baer R, Gu W (2003) Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302(5652):1972–1975. https://doi.org/10.1126/science.1091362 CrossRefPubMed

11.

Pant V, Lozano G (2014) Limiting the power of p53 through the ubiquitin proteasome pathway. Genes Dev 28(16):1739–1751. https://doi.org/10.1101/gad.247452.114 CrossRefPubMedPubMedCentral

12.

Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP (1996) Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274(5289):948–953CrossRefPubMed

13.

Momand J, Zambetti GP, Olson DC, George D, Levine AJ (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69(7):1237–1245CrossRefPubMed

14.

Rosso M, Okoro DE, Bargonetti J (2014) Splice variants of MDM2 in oncogenesis. Subcell Biochem 85:247–261. https://doi.org/10.1007/978-94-017-9211-0_14 CrossRefPubMed

15.

Bartel F, Taubert H, Harris LC (2002) Alternative and aberrant splicing of MDM2 mRNA in human cancer. Cancer Cell 2(1):9–15CrossRefPubMed

16.

Bartel F, Taylor AC, Taubert H, Harris LC (2001) Novel mdm2 splice variants identified in pediatric rhabdomyosarcoma tumors and cell lines. Oncol Res 12(11–12):451–457CrossRefPubMed

17.

Lukas J, Gao DQ, Keshmeshian M, Wen WH, Tsao-Wei D, Rosenberg S, Press MF (2001) Alternative and aberrant messenger RNA splicing of the mdm2 oncogene in invasive breast cancer. Cancer Res 61(7):3212–3219PubMed

18.

Matsumoto R, Tada M, Nozaki M, Zhang CL, Sawamura Y, Abe H (1998) Short alternative splice transcripts of the mdm2 oncogene correlate to malignancy in human astrocytic neoplasms. Cancer Res 58(4):609–613PubMed

19.

Sigalas I, Calvert AH, Anderson JJ, Neal DE, Lunec J (1996) Alternatively spliced mdm2 transcripts with loss of p53 binding domain sequences: transforming ability and frequent detection in human cancer. Nat Med 2(8):912–917CrossRefPubMed

20.

Tamborini E, Della Torre G, Lavarino C, Azzarelli A, Carpinelli P, Pierotti MA, Pilotti S (2001) Analysis of the molecular species generated by MDM2 gene amplification in liposarcomas. Int J Cancer 92(6):790–796. https://doi.org/10.1002/ijc.1271 CrossRefPubMed

21.

Fridman JS, Hernando E, Hemann MT, de Stanchina E, Cordon-Cardo C, Lowe SW (2003) Tumor promotion by Mdm2 splice variants unable to bind p53. Cancer Res 63(18):5703–5706PubMed

22.

Zheng T, Wang J, Zhao Y, Zhang C, Lin M, Wang X, Yu H, Liu L, Feng Z, Hu W (2013) Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis. Nat Commun 4:2996. https://doi.org/10.1038/ncomms3996 CrossRefPubMed

23.

Comiskey DF Jr, Jacob AG, Sanford BL, Montes M, Goodwin AK, Steiner H, Matsa E, Tapia-Santos AS, Bebee TW, Grieves J, La Perle K, Boyaka P, Chandler DS (2018) A novel mouse model of rhabdomyosarcoma underscores the dichotomy of MDM2-ALT1 function in vivo. Oncogene 37(1):95–106. https://doi.org/10.1038/onc.2017.282 CrossRefPubMed

24.

Okoro DR, Arva N, Gao C, Polotskaia A, Puente C, Rosso M, Bargonetti J (2013) Endogenous human MDM2-C is highly expressed in human cancers and functions as a p53-independent growth activator. PLoS ONE 8(10):e77643. https://doi.org/10.1371/journal.pone.0077643 CrossRefPubMedPubMedCentral

25.

Kundu N, Brekman A, Kim JY, Xiao G, Gao C, Bargonetti J (2017) Estrogen-activated MDM2 disrupts mammary tissue architecture through a p53-independent pathway. Oncotarget 8(29):47916–47930. https://doi.org/10.18632/oncotarget.18147 CrossRefPubMedPubMedCentral

26.

Dang J, Kuo ML, Eischen CM, Stepanova L, Sherr CJ, Roussel MF (2002) The RING domain of Mdm2 can inhibit cell proliferation. Cancer Res 62(4):1222–1230PubMed

27.

Evans SC, Viswanathan M, Grier JD, Narayana M, El-Naggar AK, Lozano G (2001) An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 20(30):4041–4049. https://doi.org/10.1038/sj.onc.1204533 CrossRefPubMed

28.

Manfredi JJ (2010) The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev 24(15):1580–1589. https://doi.org/10.1101/gad.1941710 CrossRefPubMedPubMedCentral

29.

Davidoff AM, Herndon JE II, Glover NS, Kerns BJ, Pence JC, Iglehart JD, Marks JR (1991) Relation between p53 overexpression and established prognostic factors in breast cancer. Surgery 110(2):259–264PubMed

30.

Davidoff AM, Kerns BJ, Iglehart JD, Marks JR (1991) Maintenance of p53 alterations throughout breast cancer progression. Can Res 51(10):2605–2610

31.

Thor AD, Moore DH, Edgerton II, Kawasaki SM, Reihsaus ES, Lynch E, Marcus HT, Schwartz JN, Chen L, Mayall LC BH, et al (1992) Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers. J Natl Cancer Inst 84(11):845–855CrossRefPubMed

32.

Anderson WF, Luo S, Chatterjee N, Rosenberg PS, Matsuno RK, Goodman MT, Hernandez BY, Reichman M, Dolled-Filhart MP, O’Regan RM, Garcia-Closas M, Perou CM, Jatoi I, Cartun RW, Sherman ME (2008) Human epidermal growth factor receptor-2 and estrogen receptor expression, a demonstration project using the residual tissue repository of the Surveillance, Epidemiology, and End Results (SEER) program. Breast Cancer Res Treat 113(1):189–196. https://doi.org/10.1007/s10549-008-9918-3 CrossRefPubMedPubMedCentral

33.

Grambsch PM, Therneau TM (1994) Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 81(3):515–526CrossRef

34.

Oliner JD, Saiki AY, Caenepeel S (2016) The role of MDM2 amplification and overexpression in tumorigenesis. Cold Spring Harb Perspect Med. https://doi.org/10.1101/cshperspect.a026336 CrossRefPubMedPubMedCentral

35.

Turbin DA, Cheang MC, Bajdik CD, Gelmon KA, Yorida E, De Luca A, Nielsen TO, Huntsman DG, Gilks CB (2006) MDM2 protein expression is a negative prognostic marker in breast carcinoma. Mod Pathol 19(1):69–74. https://doi.org/10.1038/modpathol.3800484 CrossRefPubMed

36.

Choschzick M, Heilenkotter U, Lebeau A, Jaenicke F, Terracciano L, Bokemeyer C, Sauter G, Simon R (2010) MDM2 amplification is an independent prognostic feature of node-negative, estrogen receptor-positive early-stage breast cancer. Cancer Biomark 8(2):53–60. https://doi.org/10.3233/DMA-2011-0806 CrossRefPubMed

37.

Hori M, Shimazaki J, Inagawa S, Itabashi M, Hori M (2002) Overexpression of MDM2 oncoprotein correlates with possession of estrogen receptor alpha and lack of MDM2 mRNA splice variants in human breast cancer. Breast Cancer Res Treat 71(1):77–83CrossRefPubMed

38.

Park HS, Park JM, Park S, Cho J, Kim SI, Park BW (2014) Subcellular localization of Mdm2 expression and prognosis of breast cancer. Int J Clin Oncol 19(5):842–851. https://doi.org/10.1007/s10147-013-0639-1 CrossRefPubMed

39.

Brekman A, Singh KE, Polotskaia A, Kundu N, Bargonetti J (2011) A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation. Breast Cancer Res 13(1):R3. https://doi.org/10.1186/bcr2804 CrossRefPubMedPubMedCentral

40.

Huun J, Gansmo LB, Mannsaker B, Iversen GT, Ovrebo JI, Lonning PE, Knappskog S (2017) Impact of the MDM2 splice-variants MDM2-A, MDM2-B and MDM2-C on cytotoxic stress response in breast cancer cells. BMC Cell Biol 18(1):17. https://doi.org/10.1186/s12860-017-0134-z CrossRefPubMedPubMedCentral

41.

Bond GL, Hirshfield KM, Kirchhoff T, Alexe G, Bond EE, Robins H, Bartel F, Taubert H, Wuerl P, Hait W, Toppmeyer D, Offit K, Levine AJ (2006) MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res 66(10):5104–5110. https://doi.org/10.1158/0008-5472.CAN-06-0180 CrossRefPubMed

42.

Bond GL, Hu W, Bond EE, Robins H, Lutzker SG, Arva NC, Bargonetti J, Bartel F, Taubert H, Wuerl P, Onel K, Yip L, Hwang SJ, Strong LC, Lozano G, Levine AJ (2004) A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119(5):591–602. https://doi.org/10.1016/j.cell.2004.11.022 CrossRefPubMed

43.

Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR (2015) A global reference for human genetic variation. Nature 526(7571):68–74. https://doi.org/10.1038/nature15393 CrossRef

44.

Boersma BJ, Howe TM, Goodman JE, Yfantis HG, Lee DH, Chanock SJ, Ambs S (2006) Association of breast cancer outcome with status of p53 and MDM2 SNP309. J Natl Cancer Inst 98(13):911–919. https://doi.org/10.1093/jnci/djj245 CrossRefPubMed

45.

Faur N, Araud L, Laroche-Clary A, Kanno J, Toutain J, Yamori T, Robert J, Le Morvan V (2009) The association between the T309G polymorphism of the MDM2 gene and sensitivity to anticancer drug is dependent on the p53 mutational status in cellular models. Br J Cancer 101(2):350–356. https://doi.org/10.1038/sj.bjc.6605096 CrossRefPubMedPubMedCentral

46.

van den Broek AJ, Broeks A, Horlings HM, Canisius SV, Braaf LM, Langerod A, Van’t Veer LJ, Schmidt MK (2011) Association of the germline TP53 R72P and MDM2 SNP309 variants with breast cancer survival in specific breast tumor subgroups. Breast Cancer Res Treat 130(2):599–608. https://doi.org/10.1007/s10549-011-1615-y CrossRefPubMed

47.

Harris LC (2005) MDM2 splice variants and their therapeutic implications. Curr Cancer Drug Targets 5(1):21–26CrossRefPubMed

48.

Shaikh MF, Morano WF, Lee J, Gleeson E, Babcock BD, Michl J, Sarafraz-Yazdi E, Pincus MR, Bowne WB (2016) Emerging role of MDM2 as target for anti-cancer therapy: a review. Ann Clin Lab Sci 46(6):627–634PubMed

49.

Wade M, Li YC, Wahl GM (2013) MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 13(2):83–96. https://doi.org/10.1038/nrc3430 CrossRefPubMedPubMedCentral

50.

Zhao Y, Aguilar A, Bernard D, Wang S (2015) Small-molecule inhibitors of the MDM2-p53 protein-protein interaction (MDM2 Inhibitors) in clinical trials for cancer treatment. J Med Chem 58(3):1038–1052. https://doi.org/10.1021/jm501092z CrossRefPubMed

Title: MDM2, MDM2-C, and mutant p53 expression influence breast cancer survival in a multiethnic population
Authors: Lenora W. M. Loo
Chong Gao
Yurii B. Shvetsov
Danielle R. Okoro
Brenda Y. Hernandez
Jill Bargonetti
Publication date: 01-02-2019
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2019
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-018-5065-7

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