KSBB Journal

The Korean Society for Biotechnology and Bioengineering (한국생물공학회)
권호 표지
DOI QR코드

DOI QR Code

Silencing of Mutant p53 Leads to Suppression of Human Breast Xenograft Tumor Growth in vivo

돌연변이 p53 단백질의 Silencing에 의한 사람유방암세포의 in vivo 항 종양 효과

  • Park, Won Ick (Department of Dental Pharmacology, School of Dentistry, Pusan National University) ;
  • Park, Se-Ra (Department of Dental Pharmacology, School of Dentistry, Pusan National University) ;
  • Park, Hyun-Joo (Department of Dental Pharmacology, School of Dentistry, Pusan National University) ;
  • Bae, Yun-Hee (Department of Dental Pharmacology, School of Dentistry, Pusan National University) ;
  • Ryu, Hyun Su (Department of Dental Pharmacology, School of Dentistry, Pusan National University) ;
  • Jang, Hye-Ock (Department of Dental Pharmacology, School of Dentistry, Pusan National University) ;
  • Bae, Moon-Kyoung (Department of Oral Physiology, School of Dentistry, Pusan National University) ;
  • Bae, Soo-Kyung (Department of Dental Pharmacology, School of Dentistry, Pusan National University)
  • 박원익 (부산대학교 치의학전문대학원 치과약리학교실) ;
  • 박세라 (부산대학교 치의학전문대학원 치과약리학교실) ;
  • 박현주 (부산대학교 치의학전문대학원 치과약리학교실) ;
  • 배윤희 (부산대학교 치의학전문대학원 치과약리학교실) ;
  • 유현수 (부산대학교 치의학전문대학원 치과약리학교실) ;
  • 장혜옥 (부산대학교 치의학전문대학원 치과약리학교실) ;
  • 배문경 (부산대학교 치의학전문대학원 구강생리학교실) ;
  • 배수경 (부산대학교 치의학전문대학원 치과약리학교실)
  • Received : 2016.01.18
  • Accepted : 2016.02.28
  • Published : 2016.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Mutant p53 (R280K) is highly expressed in MDA-MB-231 triple-negative human breast cancer cells. Currently, we reported the role of mutant p53-R280K in mediating the survival of MDA-MB-231 cells in vitro. The present study was undertaken to determine whether mutant p53-R280K affects breast cancer cell growth in vivo. To this end, we used small interfering RNA to knockdown the level of mutant p53-R280K in MDA-MB-231 cells. Silencing of mutant p53-R280K in MDA-MB-231 cells causes substantial tumor regression of established xenografts in vivo. In xenograft model for breast cancer, silencing of mutant p53-R280K in MDA-MB-231 cells significantly inhibited the tumor growth. Moreover, TUNEL assay showed more occurrence of apoptotic cells in mutant p53-R280K silenced tumors compared to control. Our data indicate that mutant p53-R280K has an important role in mediating tumor growth of MDA-MB-231 cells in vivo. Taken together, this study suggests that endogenous mutant p53-R280K could be used as a therapeutic target for breast cancer cells harboring this TP53 missense mutation.

Keywords

References

  1. Selivanova, G. (2004) P53: Fighting Cancer. Curr. Cancer. Drug Targets 4: 385-402. https://doi.org/10.2174/1568009043332934
  2. Horn, H. F. and K. H. Vousden (2007) Coping with stress: multiple ways to activate p53. Oncogene. 26: 1306-1316. https://doi.org/10.1038/sj.onc.1210263
  3. Molchadsky, A., N. Rivlin, R. Brosh, V. Rotter, and R. Sarig (2010) P53 is balancing development, differentiation and de-differentiation to assure cancer prevention. Carcinogenesis. 31: 1501-1508. https://doi.org/10.1093/carcin/bgq101
  4. Brosh, R. and V. Rotter (2009) When mutants gain new powers: news from the mutant p53 field. Nat. Rev. Cancer. 9: 701-713. https://doi.org/10.1038/nrc2693
  5. Walerych, D., M. Napoli, L. Collavin, and G. Del-Sal (2012) The rebel angel: mutant p53 as the driving oncogene in breast cancer. Carcinogenesis. 33: 2007-2017. https://doi.org/10.1093/carcin/bgs232
  6. Wijnhoven, S. W., E. N. Speksnijder, X. Liu, E. Zwart, C. T. van Oostrom, R. B. Beems, E. M. Hoogervorst, M. M. Schaap, L. D. Attardi, T. Jacks, H. van Steeg, J. Jonkers, and A. deVries (2007) Dominant-negative but not gain-of-function effects of a p53.R270H mutation in mouse epithelium tissue after DNA damage. Cancer Res. 67: 4648-4656. https://doi.org/10.1158/0008-5472.CAN-06-4681
  7. Mehta, S. A., K. W. Christopherson, P. Bhat-Nakshatri, J. R. Goulet-RJ, H. E. Broxmeyer, L. Kopelovich, and H. Nakshatri (2007) Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion. Oncogene. 26: 3329-3337. https://doi.org/10.1038/sj.onc.1210120
  8. Zhu, H. B., K. Yang, Y. Q. Xie, Y. W. Lin, Q. Q. Mao, and L. P. Xie (2013) Silencing of mutant p53 by siRNA induces cell cycle arrest and apoptosis in human bladder cancer cells. World J. Surg. Oncol. 28: 11-22.
  9. Lim, L. Y., N. Vidnovic, L. W. Ellisen, and C. O. Leong (2009) Mutant p53 mediates survival of breast cancer cells. Br. J. Cancer. 101: 1606-1612. https://doi.org/10.1038/sj.bjc.6605335
  10. Bayraktar, S. and S. Gluck (2013) Molecularly targeted therapies for metastatic triple-negative breast cancer. Breast Cancer Res. Treat. 138: 21-35. https://doi.org/10.1007/s10549-013-2421-5
  11. Bae, Y. H., J. H. Ryu, H. J. Park, K. R. Kim, H. J. Wee, O. H. Lee, H. O. Jang, M. K. Bae, K. W. Kim, and S. K. Bae (2013) Mutant p53-notch1 signaling axis is involved in curcumin-induced apoptosis of breast cancer cells. Korean J. Physiol. Pharmacol. 17: 291-297. https://doi.org/10.4196/kjpp.2013.17.4.291
  12. Bae, Y. H., J. M. Shin, H. J. Park, H. O. Jang, M. K. Bae, and S. K. Bae (2014) Gain-of-function mutant p53-R280K mediates survival of breast cancer cells. Genes & Genomics 36: 171-178. https://doi.org/10.1007/s13258-013-0154-9