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Nucleostemin reveals a dichotomous nature of genome maintenance in mammary tumor progression

Oncogene volume 38, pages 3919–3931 (2019)Cite this article

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Abstract

A defective homologous recombination (HR) repair program increases tumor incidence as well as providing a survival advantage in patients with breast and ovarian cancers. Here we hypothesize that the tumor-promoting side of genome maintenance programs may be contributed by a self-renewal protein, nucleostemin (NS). To address this issue, we established its functional importance in mammary tumor progression in mice and showed that mammary tumor cells become highly susceptible to replicative DNA damage following NS depletion and are protected from hydroxyurea-induced damage by NS overexpression. Breast cancer cells with basal-like characters display more reliance on NS for genome maintenance than those with luminal characters. Mechanistically, NS-deficient cells demonstrate a significantly reduced HR repair activity. TCGA analyses of human breast cancers revealed that NS is co-enriched positively with HR repair proteins and that high NS expression correlates with low HR defects and predicts poor progression-free survival and resistance to knockdown of cell-cycle checkpoint genes in triple-negative/basal-like breast cancers. This work indicates that NS constitutes a tumor-promoting genome maintenance program required for mammary tumor progression.

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References

  1. Lindahl T, Barnes DE. Repair of endogenous DNA damage. Cold Spring Harb Symp Quant Biol. 2000;65:127–33.

    Article  CAS  Google Scholar 

  2. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010;40:179–204.

    Article  CAS  Google Scholar 

  3. Loeb LA, Springgate CF, Battula N. Errors in DNA replication as a basis of malignant changes. Cancer Res. 1974;34:2311–21.

    CAS  PubMed  Google Scholar 

  4. Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375:443–53.

    Article  CAS  Google Scholar 

  5. Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 2016;534:47–54.

    Article  CAS  Google Scholar 

  6. Tubbs A, Nussenzweig A, Endogenous DNA. Damage as a source of genomic instability in. Cancer Cell. 2017;168:644–56.

    CAS  Google Scholar 

  7. Michel B, Grompone G, Flores MJ, Bidnenko V. Multiple pathways process stalled replication forks. Proc Natl Acad Sci USA. 2004;101:12783–8.

    Article  CAS  Google Scholar 

  8. Graeser M, McCarthy A, Lord CJ, Savage K, Hills M, Salter J, et al. A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin Cancer Res. 2010;16:6159–68.

    Article  CAS  Google Scholar 

  9. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34.

    Article  CAS  Google Scholar 

  10. Wiedemeyer WR, Beach JA, Karlan BY. Reversing platinum resistance in high-grade serous ovarian carcinoma: targeting brca and the homologous recombination system. Front Oncol. 2014;4:34.

    Article  Google Scholar 

  11. Peng G, Chun-Jen Lin C, Mo W, Dai H, Park YY, Kim SM, et al. Genome-wide transcriptome profiling of homologous recombination DNA repair. Nat Commun. 2014;5:3361.

    Article  Google Scholar 

  12. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov. 2015;5:1137–54.

    Article  CAS  Google Scholar 

  13. Tsai RY, McKay RD. A nucleolar mechanism controlling cell proliferation in stem cells and cancer cells. Genes Dev. 2002;16:2991–3003.

    Article  CAS  Google Scholar 

  14. Baddoo M, Hill K, Wilkinson R, Gaupp D, Hughes C, Kopen GC, et al. Characterization of mesenchymal stem cells isolated from murine bone marrow by negative selection. J Cell Biochem. 2003;89:1235–49.

    Article  CAS  Google Scholar 

  15. Lin T, Meng L, Li Y, Tsai RY. Tumor-initiating function of nucleostemin-enriched mammary tumor cells. Cancer Res. 2010;70:9444–52.

    Article  CAS  Google Scholar 

  16. Qu J, Bishop JM. Nucleostemin maintains self-renewal of embryonic stem cells and promotes reprogramming of somatic cells to pluripotency. J Cell Biol. 2012;197:731–45.

    Article  CAS  Google Scholar 

  17. Zhu Q, Yasumoto H, Tsai RY. Nucleostemin delays cellular senescence and negatively regulates TRF1 protein stability. Mol Cell Biol. 2006;26:9279–90.

    Article  CAS  Google Scholar 

  18. Meng L, Lin T, Peng G, Hsu JK, Lee S, Lin S-Y, et al. Nucleostemin deletion reveals an essential mechanism that maintains the genomic stability of stem and progenitor cells. Proc Natl Acad Sci USA. 2013;110:11415–20.

    Article  CAS  Google Scholar 

  19. Tsai RY. New frontiers in nucleolar research: nucleostemin and related proteins. The Nucleolus (Protein Reviews15) 2011:301–20.

  20. Lin T, Ibrahim W, Peng C-Y, Finegold MJ, Tsai RY. A novel role of nucleostemin in maintaining the genome integrity of dividing hepatocytes during mouse liver development and regeneration. Hepatology. 2013;58:2176–87.

    Article  CAS  Google Scholar 

  21. Hsu JK, Lin T, Tsai RY. Nucleostemin prevents telomere damage by promoting PML-IV recruitment to SUMOylated TRF1. J Cell Biol. 2012;197:613–24.

    Article  CAS  Google Scholar 

  22. Lin T, Meng L, Wu LJ, Pederson T, Tsai RY. Nucleostemin and GNL3L exercise distinct functions in genome protection and ribosome synthesis, respectively. J Cell Sci. 2014;127:2302–12.

    Article  CAS  Google Scholar 

  23. Tsai RY. Turning a new page on nucleostemin and self-renewal. J Cell Sci. 2014;127:3885–91.

    Article  CAS  Google Scholar 

  24. Tsai RY, Meng L. Nucleostemin: a latecomer with new tricks. Int J Biochem Cell Biol. 2009;41:2122–4.

    Article  CAS  Google Scholar 

  25. Tsai RY. Balancing self-renewal against genome preservation in stem cells: How do they manage to have the cake and eat it too? Cell Mol life Sci: CMLS. 2016;73:1803–23.

    Article  CAS  Google Scholar 

  26. Kobayashi T, Masutomi K, Tamura K, Moriya T, Yamasaki T, Fujiwara Y, et al. Nucleostemin expression in invasive breast cancer. BMC Cancer. 2014;14:215.

    Article  Google Scholar 

  27. Meng L, Lin T, Tsai RY. Nucleoplasmic mobilization of nucleostemin stabilizes MDM2 and promotes G2-M progression and cell survival. J Cell Sci. 2008;121:4037–46.

    Article  CAS  Google Scholar 

  28. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.

    Article  CAS  Google Scholar 

  29. Sheridan C, Kishimoto H, Fuchs RK, Mehrotra S, Bhat-Nakshatri P, Turner CH, et al. CD44+/CD24– breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 2006;8:R59.

    Article  Google Scholar 

  30. Phillips TM, McBride WH, Pajonk F. The response of CD24(–/low)/CD44+breast cancer-initiating cells to radiation. J Natl Cancer Inst. 2006;98:1777–85.

    Article  Google Scholar 

  31. Fillmore CM, Kuperwasser C. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 2008;10:R25.

    Article  Google Scholar 

  32. Dai MS, Sun XX, Lu H. Aberrant expression of nucleostemin activates p53 and induces cell cycle arrest via inhibition of MDM2. Mol Cell Biol. 2008;28:4365–76.

    Article  CAS  Google Scholar 

  33. Lo D, Lu H. Nucleostemin: Another nucleolar “Twister” of the p53-MDM2 loop. Cell Cycle. 2010;9:3227–32.

    Article  CAS  Google Scholar 

  34. Huang G, Meng L, Tsai RY. p53 configures the G2/M arrest response of nucleostemin-deficient cells. Cell Death Discov. 2015;1:e15060.

    Article  Google Scholar 

  35. O’Connell BC, Cheung AF, Simkevich CP, Tam W, Ren X, Mateyak MK, et al. A large scale genetic analysis of c-Myc-regulated gene expression patterns. J Biol Chem. 2003;278:12563–73.

    Article  Google Scholar 

  36. Zwolinska AK, Heagle Whiting A, Beekman C, Sedivy JM, Marine JC. Suppression of Myc oncogenic activity by nucleostemin haploinsufficiency. Oncogene. 2012;31:3311–21.

    Article  CAS  Google Scholar 

  37. Mertins P, Mani DR, Ruggles KV, Gillette MA, Clauser KR, Wang P, et al. Proteogenomics connects somatic mutations to signalling in breast cancer. Nature. 2016;534:55–62.

    Article  CAS  Google Scholar 

  38. Bennardo N, Cheng A, Huang N, Stark JM. Alternative-NHEJ is a mechanistically distinct pathway of mammalian chromosome break repair. PLoS Genet. 2008;4:e1000110.

    Article  Google Scholar 

  39. Bennardo N, Gunn A, Cheng A, Hasty P, Stark JM. Limiting the persistence of a chromosome break diminishes its mutagenic potential. PLoS Genet. 2009;5:e1000683.

    Article  Google Scholar 

  40. Gunn A, Stark JM. I-SceI-based assays to examine distinct repair outcomes of mammalian chromosomal double strand breaks. Methods Mol Biol. 2012;920:379–91.

    Article  CAS  Google Scholar 

  41. Gunn A, Bennardo N, Cheng A, Stark JM. Correct end use during end joining of multiple chromosomal double strand breaks is influenced by repair protein RAD50, DNA-dependent protein kinase DNA-PKcs, and transcription context. J Biol Chem. 2011;286:42470–82.

    Article  CAS  Google Scholar 

  42. Etienne MC, Milano G, Fischel JL, Frenay M, Francois E, Formento JL, et al. Tamoxifen metabolism: pharmacokinetic and in vitro study. Br J Cancer. 1989;60:30–5.

    Article  CAS  Google Scholar 

  43. Watkins JA, Irshad S, Grigoriadis A, Tutt AN. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res: BCR. 2014;16:211.

    Article  Google Scholar 

  44. Knijnenburg TA, Wang L, Zimmermann MT, Chambwe N, Gao GF, Cherniack AD, et al. Genomic and molecular landscape of DNA damage repair deficiency across the cancer genome atlas. Cell Rep. 2018;23:239–54.

    Article  CAS  Google Scholar 

  45. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4.

    Article  Google Scholar 

  46. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The cancer cell line encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7.

    Article  CAS  Google Scholar 

  47. Seashore-Ludlow B, Rees MG, Cheah JH, Cokol M, Price EV, Coletti ME, et al. Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset. Cancer Discov. 2015;5:1210–23.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Margie Moczygemba at the IBT Flow Cytometry Core for her help in cell cycle analysis. This work was supported by NCI-PHS grants (R01 CA113750, R03 CA201988, R21AG052006) to RYT, National Science Council Postdoctoral Fellowship (ROC) to TCL, G. Komen PDF17483544 to DJM, and CPRIT RP140456 to GP.

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  1. These authors contributed equally: Daniel J. McGrail and Parnit K. Bhupal

Authors and Affiliations

  1. Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA

    Tao Lin, Tsung-Chin Lin, Parnit K. Bhupal, Yi-Hsuan Ku, Wen Zhang, Lingjun Meng & Robert Y. L. Tsai

  2. Department of Systems Biology, MD Anderson Cancer Center, Houston, TX, USA

    Daniel J. McGrail & Shiaw-Yih Lin

  3. Department of Clinical Cancer Prevention, MD Anderson Cancer Center, Houston, TX, USA

    Guang Peng

  4. Department of Molecular and Cellular Medicine, Texas A&M University, College Station, TX, USA

    Robert Y. L. Tsai

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  1. Tao Lin
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Lin, T., Lin, TC., McGrail, D.J. et al. Nucleostemin reveals a dichotomous nature of genome maintenance in mammary tumor progression. Oncogene 38, 3919–3931 (2019). https://doi.org/10.1038/s41388-019-0710-0

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