CoChat
Sign Up
Cited by 71

A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation

Brekman, Angelika, Singh, Kathryn E, Polotskaia, Alla, Kundu, Nandini, Bargonetti, Jill·2011·Breast Cancer Research
DOI 10.1186/bcr2804PMC PMC3109566
Open this paper in CoChat — free account

Abstract

Introduction: Estrogen receptor positive breast cancers often have high levels of Mdm2. We investigated if estrogen signaling in such breast cancers occurred through an Mdm2 mediated pathway with subsequent inactivation of p53. Methods: We examined the effect of long-term 17β-estradiol (E2) treatment (five days) on the p53-Mdm2 pathway in estrogen receptor alpha (ERα) positive breast cancer cell lines that contain wild-type p53 (MCF-7 and ZR75-1). We assessed the influence of estrogen by examining cell proliferation changes, activation of transcription of p53 target genes, p53-chromatin interactions and cell cycle profile changes. To determine the effects of Mdm2 and p53 knockdown on the estrogen-mediated proliferation signals we generated MCF-7 cell lines with inducible shRNA for mdm2 or p53 and monitored their influence on estrogen-mediated outcomes. To further address the p53-independent effect of Mdm2 in ERα positive breast cancer we generated cell lines with inducible shRNA to mdm2 using the mutant p53 expressing cell line T-47D. Results: Estrogen increased the Mdm2 protein level in MCF-7 cells without decreasing the p53 protein level. After estrogen treatment of MCF-7 cells, down-regulation of basal transcription of p53 target genes puma and p21 was observed. Estrogen treatment also down-regulated etoposide activated transcription of puma, but not p21. Mdm2 knockdown in MCF-7 cells increased p21 mRNA and protein, decreased cell growth in 3D matrigel and also decreased estrogen-induced cell proliferation in 2D culture. In contrast, knockdown of p53 had no effect on estrogen-induced cell proliferation. In T-47D cells with mutant p53, the knockdown of Mdm2 decreased estrogen-mediated cell proliferation but did not increase p21 protein. Conclusions: Estrogen-induced breast cancer cell proliferation required a p53-independent role of Mdm2. The combined influence of genetic and environmental factors on the tumor promoting effects of estrogen implicated Mdm2 as a strong contributor to the bypass of cell cycle checkpoints. The novel finding that p53 was not the key target of Mdm2 in the estrogen activation of cell proliferation could have great benefit for future Mdm2-targeted breast cancer therapies.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/bcr2804

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 57

  1. Vogelstein B Lane D Levine AJ Surfing the p53 network Nature 2000 408 307 310 10.1038/35042675 11099028 · DOI · Paper page
  2. Lacroix M Toillon RA Leclercq G p53 and breast cancer, an update Endocr Relat Cancer 2006 13 293 325 10.1677/erc.1.01172 16728565 · DOI
  3. Pharoah PD Day NE Caldas C Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis Br J Cancer 1999 80 1968 1973 10.1038/sj.bjc.6690628 10471047 PMC2363143 · DOI
  4. Hartmann A Blaszyk H Kovach JS Sommer SS The molecular epidemiology of p53 gene mutations in human breast cancer Trends Genet 1997 13 27 33 10.1016/S0168-9525(96)10043-3 9009845 · DOI
  5. Momand J Jung D Wilczynski S Niland J The MDM2 gene amplification database Nucleic Acids Res 1998 26 3453 3459 10.1093/nar/26.15.3453 9671804 PMC147746 · DOI · Paper page
  6. Sheikh MS Shao Z Hussain A Fontana JA The p53-binding protein MDM2 gene is differentially expressed in human breast carcinoma Cancer Res 1993 53 3226 3228 8324731
  7. Phelps M Darley M Primrose JN Blaydes JP p53-independent activation of the hdm2-P2 promoter through multiple transcription factor response elements results in elevated hdm2 expression in estrogen receptor alpha-positive breast cancer cells Cancer Res 2003 63 2616 2623 12750288
  8. Martin M Molecular biology of breast cancer Clin Transl Oncol 2006 8 7 14 10.1007/s12094-006-0089-6 16632434 · DOI
  9. Pearce ST Jordan VC The biological role of estrogen receptors alpha and beta in cancer Crit Rev Oncol Hematol 2004 50 3 22 10.1016/j.critrevonc.2003.09.003 15094156 · DOI
  10. Rodrik V Zheng Y Harrow F Chen Y Foster DA Survival signals generated by estrogen and phospholipase D in MCF-7 breast cancer cells are dependent on Myc Mol Cell Biol 2005 25 7917 7925 10.1128/MCB.25.17.7917-7925.2005 16107734 PMC1190308 · DOI
  11. Perillo B Sasso A Abbondanza C Palumbo G 17beta-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence Mol Cell Biol 2000 20 2890 2901 10.1128/MCB.20.8.2890-2901.2000 10733592 PMC85519 · DOI
  12. Liu W Konduri SD Bansal S Nayak BK Rajasekaran SA Karuppayil SM Rajasekaran AK Das GM Estrogen receptor-alpha binds p53 tumor suppressor protein directly and represses its function J Biol Chem 2006 281 9837 9840 10.1074/jbc.C600001200 16469747 · DOI
  13. Sayeed A Konduri SD Liu W Bansal S Li F Das GM Estrogen receptor alpha inhibits p53-mediated transcriptional repression: implications for the regulation of apoptosis Cancer Res 2007 67 7746 7755 10.1158/0008-5472.CAN-06-3724 17699779 · DOI
  14. Hu W Feng Z Ma L Wagner J Rice JJ Stolovitzky G Levine AJ A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells Cancer Res 2007 67 2757 2765 10.1158/0008-5472.CAN-06-2656 17363597 · DOI
  15. Lukas J Gao DQ Keshmeshian M Wen WH Tsao-Wei D Rosenberg S Press MF Alternative and aberrant messenger RNA splicing of the mdm2 oncogene in invasive breast cancer Cancer Res 2001 61 3212 3219 11306511
  16. Turbin DA Cheang MC Bajdik CD Gelmon KA Yorida E De Luca A Nielsen TO Huntsman DG Gilks CB MDM2 protein expression is a negative prognostic marker in breast carcinoma Mod Pathol 2006 19 69 74 10.1038/modpathol.3800484 16258514 · DOI
  17. Kinyamu HK Archer TK Estrogen receptor-dependent proteasomal degradation of the glucocorticoid receptor is coupled to an increase in mdm2 protein expression Mol Cell Biol 2003 23 5867 5881 10.1128/MCB.23.16.5867-5881.2003 12897156 PMC166332 · DOI
  18. Saji S Okumura N Eguchi H Nakashima S Suzuki A Toi M Nozawa Y Hayashi S MDM2 enhances the function of estrogen receptor alpha in human breast cancer cells Biochem Biophys Res Commun 2001 281 259 265 10.1006/bbrc.2001.4339 11178989 · DOI
  19. 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 A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans Cell 2004 119 591 602 10.1016/j.cell.2004.11.022 15550242 · DOI · Paper page
  20. Arva NC Gopen TR Talbott KE Campbell LE Chicas A White DE Bond GL Levine AJ Bargonetti J A chromatin associated and transcriptionally inactive p53-MDM2 complex occurs in MDM2 SNP 309 homozygous cells J Biol Chem 2005 280 26776 26787 10.1074/jbc.M505203200 15908423 · DOI
  21. Juven T Barak Y Zauberman A George DL Oren M Wild type p53 can mediate sequence-specific transactivation of an internal promoter within the mdm2 gene Oncogene 1993 8 3411 3416 8247544
  22. Oren M Damalas A Gottlieb T Michael D Taplick J Leal JF Maya R Moas M Seger R Taya Y Ben-Ze'ev A Regulation of p53: intricate loops and delicate balances Biochem Pharmacol 2002 64 865 871 10.1016/S0006-2952(02)01149-8 12213580 · DOI
  23. Moll UM Petrenko O The MDM2-p53 interaction Mol Cancer Res 2003 1 1001 1008 14707283
  24. Oliner JD Pietenpol JA Thiagalingam S Gyuris J Kinzler KW Vogelstein B Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53 Nature 1993 362 857 860 10.1038/362857a0 8479525 · DOI
  25. Wu X Bayle JH Olson D Levine AJ The p53-mdm-2 autoregulatory feedback loop Genes Dev 1993 7 1126 1132 10.1101/gad.7.7a.1126 8319905 · DOI · Paper page
  26. Thut CJ Goodrich JA Tjian R Repression of p53-mediated transcription by MDM2: a dual mechanism Genes Dev 1997 11 1974 1986 10.1101/gad.11.15.1974 9271120 PMC316412 · DOI · Paper page
  27. Jin Y Lee H Zeng SX Dai MS Lu H MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation Embo J 2003 22 6365 6377 10.1093/emboj/cdg600 14633995 PMC291841 · DOI · Paper page
  28. Vazquez A Bond EE Levine AJ Bond GL The genetics of the p53 pathway, apoptosis and cancer therapy Nat Rev Drug Discov 2008 7 979 987 10.1038/nrd2656 19043449 · DOI
  29. Vousden KH Lane DP p53 in health and disease Nat Rev Mol Cell Biol 2007 8 275 283 10.1038/nrm2147 17380161 · DOI
  30. Chipuk JE Bouchier-Hayes L Kuwana T Newmeyer DD Green DR PUMA couples the nuclear and cytoplasmic proapoptotic function of p53 Science 2005 309 1732 1735 10.1126/science.1114297 16151013 · DOI
  31. Jordan VC O'Malley BW Selective estrogen-receptor modulators and antihormonal resistance in breast cancer J Clin Oncol 2007 25 5815 5824 10.1200/JCO.2007.11.3886 17893378 · DOI
  32. Kaeser MD Iggo RD Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo Proc Natl Acad Sci USA 2002 99 95 100 10.1073/pnas.012283399 11756653 PMC117520 · DOI
  33. Lev Bar-Or R Maya R Segel LA Alon U Levine AJ Oren M Generation of oscillations by the p53-Mdm2 feedback loop: a theoretical and experimental study Proc Natl Acad Sci USA 2000 97 11250 11255 10.1073/pnas.210171597 11016968 PMC17186 · DOI
  34. Rodrik V Gomes E Hui L Rockwell P Foster DA Myc stabilization in response to estrogen and phospholipase D in MCF-7 breast cancer cells FEBS Lett 2006 580 5647 5652 10.1016/j.febslet.2006.09.013 16996503 PMC1876739 · DOI
  35. Shanmugam M Krett NL Maizels ET Cutler RE Jr Peters CA Smith LM O'Brien ML Park-Sarge OK Rosen ST Hunzicker-Dunn M Regulation of protein kinase C delta by estrogen in the MCF-7 human breast cancer cell line Mol Cell Endocrinol 1999 148 109 118 10.1016/S0303-7207(98)00229-9 10221776 · DOI
  36. Moll UM Riou G Levine AJ Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion Proc Natl Acad Sci USA 1992 89 7262 7266 10.1073/pnas.89.15.7262 1353891 PMC49686 · DOI
  37. Molinari AM Bontempo P Schiavone EM Tortora V Verdicchio MA Napolitano M Nola E Moncharmont B Medici N Nigro V Armetta I Abbondanza C Puca GA Estradiol induces functional inactivation of p53 by intracellular redistribution Cancer Res 2000 60 2594 2597 10825127
  38. Bissell MJ Radisky DC Rizki A Weaver VM Petersen OW The organizing principle: microenvironmental influences in the normal and malignant breast Differentiation 2002 70 537 546 10.1046/j.1432-0436.2002.700907.x 12492495 PMC2933198 · DOI
  39. Kenny PA Lee GY Myers CA Neve RM Semeiks JR Spellman PT Lorenz K Lee EH Barcellos-Hoff MH Petersen OW Gray JW Bissell MJ The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression Mol Oncol 2007 1 84 96 10.1016/j.molonc.2007.02.004 18516279 PMC2391005 · DOI · Paper page
  40. Gudas JM Oka M Diella F Trepel J Cowan KH Expression of wild-type p53 during the cell cycle in normal human mammary epithelial cells Cell Growth Differ 1994 5 295 304 8018562
  41. Hori M Shimazaki J Inagawa S Itabashi M 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 2002 71 77 83 10.1023/A:1013350419426 11859876 · DOI
  42. Paris R Henry RE Stephens SJ McBryde M Espinosa JM Multiple p53-independent gene silencing mechanisms define the cellular response to p53 activation Cell Cycle 2008 7 2427 2433 18677110 PMC2926973
  43. Espinosa JM Mechanisms of regulatory diversity within the p53 transcriptional network Oncogene 2008 27 4013 4023 10.1038/onc.2008.37 18278067 PMC2914794 · DOI
  44. Tozlu S Girault I Vacher S Vendrell J Andrieu C Spyratos F Cohen P Lidereau R Bieche I Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach Endocr Relat Cancer 2006 13 1109 1120 10.1677/erc.1.01120 17158757 · DOI
  45. Mobley JA Brueggemeier RW Estrogen receptor-mediated regulation of oxidative stress and DNA damage in breast cancer Carcinogenesis 2004 25 3 9 10.1093/carcin/bgg175 14514655 · DOI
  46. Chen Y Liu X Pisha E Constantinou AI Hua Y Shen L van Breemen RB Elguindi EC Blond SY Zhang F Bolton JL A metabolite of equine estrogens, 4-hydroxyequilenin, induces DNA damage and apoptosis in breast cancer cell lines Chem Res Toxicol 2000 13 342 350 10.1021/tx990186j 10813650 · DOI
  47. Yared E McMillan TJ Martin FL Genotoxic effects of oestrogens in breast cells detected by the micronucleus assay and the Comet assay Mutagenesis 2002 17 345 352 10.1093/mutage/17.4.345 12110632 · DOI
  48. Metivier R Gallais R Tiffoche C Le Peron C Jurkowska RZ Carmouche RP Ibberson D Barath P Demay F Reid G Benes V Jeltsch A Gannon F Salbert G Cyclical DNA methylation of a transcriptionally active promoter Nature 2008 452 45 50 10.1038/nature06544 18322525 · DOI
  49. Kangaspeska S Stride B Metivier R Polycarpou-Schwarz M Ibberson D Carmouche RP Benes V Gannon F Reid G Transient cyclical methylation of promoter DNA Nature 2008 452 112 115 10.1038/nature06640 18322535 · DOI
  50. Zhang S Cao HJ Davis FB Tang HY Davis PJ Lin HY Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cells Br J Cancer 2004 91 178 185 10.1038/sj.bjc.6601902 15188005 PMC2364738 · DOI
  51. Jin Y Zeng SX Dai MS Yang XJ Lu H MDM2 inhibits PCAF (p300/CREB-binding protein-associated factor)-mediated p53 acetylation J Biol Chem 2002 277 30838 30843 10.1074/jbc.M204078200 12068014 · DOI
  52. Jin Y Zeng SX Lee H Lu H MDM2 mediates p300/CREB-binding protein-associated factor ubiquitination and degradation J Biol Chem 2004 279 20035 20043 10.1074/jbc.M309916200 14769800 · DOI
  53. Iyer NG Chin SF Ozdag H Daigo Y Hu DE Cariati M Brindle K Aparicio S Caldas C p300 regulates p53-dependent apoptosis after DNA damage in colorectal cancer cells by modulation of PUMA/p21 levels Proc Natl Acad Sci USA 2004 101 7386 7391 10.1073/pnas.0401002101 15123817 PMC409928 · DOI
  54. Sun SH Zheng M Ding K Wang S Sun Y A small molecule that disrupts Mdm2-p53 binding activates p53, induces apoptosis, and sensitizes lung cancer cells to chemotherapy Cancer Biol Ther 2008 7 18340116
  55. Fernandez PC Frank SR Wang L Schroeder M Liu S Greene J Cocito A Amati B Genomic targets of the human c-Myc protein Genes Dev 2003 17 1115 1129 10.1101/gad.1067003 12695333 PMC196049 · DOI
  56. Mumcuoglu M Bagislar S Yuzugullu H Alotaibi H Senturk S Telkoparan P Gur-Dedeoglu B Cingoz B Bozkurt B Tazebay UH Yulug IG Akcali KC Ozturk M The ability to generate senescent progeny as a mechanism underlying breast cancer cell heterogeneity PLoS One 2010 5 e11288 10.1371/journal.pone.0011288 20585577 PMC2891998 · DOI
  57. Sun P Dong P Dai K Hannon GJ Beach D p53-independent role of MDM2 in TGF-beta1 resistance Science 1998 282 2270 2272 10.1126/science.282.5397.2270 9856953 · DOI

Cited by

Sorted by citations

Authors
Brekman, A., Singh, K. E., Polotskaia, A., Kundu, N., & Bargonetti, J.
Venue
Breast Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2011-01-11
Volume
13
Issue
1
ISSN
1465-542X
DOI
10.1186/bcr2804
PMC
PMC3109566
Cited by
71
References
3
Language
en
Update notices
correction (2012-02-29)
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review