Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Science Signaling - Call For Papers

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 5 July 2002:
Vol. 297. no. 5578, pp. 102 - 104
DOI: 10.1126/science.1071489
Prev | Table of Contents | Next

Reports

Sustained Loss of a Neoplastic Phenotype by Brief Inactivation of MYC

Meenakshi Jain,1* Constadina Arvanitis,1* Kenneth Chu,2 William Dewey,2 Edith Leonhardt,2 Maxine Trinh,2 Christopher D. Sundberg,1 J. Michael Bishop,3 Dean W. Felsher1dagger

Pharmacological inactivation of oncogenes is being investigated as a possible therapeutic strategy for cancer. One potential drawback is that cessation of such therapy may allow reactivation of the oncogene and tumor regrowth. We used a conditional transgenic mouse model for MYC-induced tumorigenesis to demonstrate that brief inactivation of MYC results in the sustained regression of tumors and the differentiation of osteogenic sarcoma cells into mature osteocytes. Subsequent reactivation of MYC did not restore the cells' malignant properties but instead induced apoptosis. Thus, brief MYC inactivation appears to cause epigenetic changes in tumor cells that render them insensitive to MYC-induced tumorigenesis. These results raise the possibility that transient inactivation of MYC may be an effective therapy for certain cancers.

1 Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA 94305-5151, USA.
2 Department of Radiation Oncology, University of California, San Francisco, CA 94143-0806, USA.
3 G. W. Hooper Foundation, University of California, San Francisco, CA 94143-0552, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: dfelsher{at}leland.stanford.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Genomic and Proteomic Analysis Reveals a Threshold Level of MYC Required for Tumor Maintenance.
C. M. Shachaf, A. J. Gentles, S. Elchuri, D. Sahoo, Y. Soen, O. Sharpe, O. D. Perez, M. Chang, D. Mitchel, W. H. Robinson, et al. (2008)
Cancer Res. 68, 5132-5142
   Abstract »    Full Text »    PDF »
Suppression of proHB-EGF Carboxy-Terminal Fragment Nuclear Translocation: A New Molecular Target Therapy for Gastric Cancer.
T. Shimura, H. Kataoka, N. Ogasawara, E. Kubota, M. Sasaki, S. Tanida, and T. Joh (2008)
Clin. Cancer Res. 14, 3956-3965
   Abstract »    Full Text »    PDF »
Oncogene Addiction versus Oncogene Amnesia: Perhaps More than Just a Bad Habit?.
D. W. Felsher, I. B. Weinstein, and A. Joe (2008)
Cancer Res. 68, 3081-3086
   Abstract »    Full Text »    PDF »
Oncogene cooperation in tumor maintenance and tumor recurrence in mouse mammary tumors induced by Myc and mutant Kras.
K. Podsypanina, K. Politi, L. J. Beverly, and H. E. Varmus (2008)
PNAS 105, 5242-5247
   Abstract »    Full Text »    PDF »
Oncogene addiction: setting the stage for molecularly targeted cancer therapy.
S. V. Sharma and J. Settleman (2007)
Genes & Dev. 21, 3214-3231
   Abstract »    Full Text »    PDF »
MicroRNA Let-7a Down-regulates MYC and Reverts MYC-Induced Growth in Burkitt Lymphoma Cells.
V. B. Sampson, N. H. Rong, J. Han, Q. Yang, V. Aris, P. Soteropoulos, N. J. Petrelli, S. P. Dunn, and L. J. Krueger (2007)
Cancer Res. 67, 9762-9770
   Abstract »    Full Text »    PDF »
Notch1 co-opts lymphoid enhancer factor 1 for survival of murine T-cell lymphomas.
C. Spaulding, E. J. Reschly, D. E. Zagort, Y. Yashiro-Ohtani, L. J. Beverly, A. Capobianco, W. S. Pear, and B. L. Kee (2007)
Blood 110, 2650-2658
   Abstract »    Full Text »    PDF »
Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis.
C. M. Shachaf, O. D. Perez, S. Youssef, A. C. Fan, S. Elchuri, M. J. Goldstein, A. E. Shirer, O. Sharpe, J. Chen, D. J. Mitchell, et al. (2007)
Blood 110, 2674-2684
   Abstract »    Full Text »    PDF »
Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation.
C.-H. Wu, J. van Riggelen, A. Yetil, A. C. Fan, P. Bachireddy, and D. W. Felsher (2007)
PNAS 104, 13028-13033
   Abstract »    Full Text »    PDF »
Validating Oncogenes as Therapeutic Targets Using Conditional Transgenic Models.
D. W. Felsher (2007)
Am. Assoc. Cancer Res. Educ. Book 2007, 27-36
   Full Text »    PDF »
WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells.
W. A. Woodward, M. S. Chen, F. Behbod, M. P. Alfaro, T. A. Buchholz, and J. M. Rosen (2007)
PNAS 104, 618-623
   Abstract »    Full Text »    PDF »
Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch.
S. Giuriato, S. Ryeom, A. C. Fan, P. Bachireddy, R. C. Lynch, M. J. Rioth, J. van Riggelen, A. M. Kopelman, E. Passegue, F. Tang, et al. (2006)
PNAS 103, 16266-16271
   Abstract »    Full Text »    PDF »
Developing gene expression signatures of pathway deregulation in tumors..
J. W. Watters and C. J. Roberts (2006)
Mol. Cancer Ther. 5, 2444-2449
   Abstract »    Full Text »    PDF »
Identification of small molecules that induce apoptosis in a Myc-dependent manner and inhibit Myc-driven transformation.
H. Mo and M. Henriksson (2006)
PNAS 103, 6344-6349
   Abstract »    Full Text »    PDF »
MYC Amplification and Polysomy 8 in Chondrosarcoma: Array Comparative Genomic Hybridization, Fluorescent In Situ Hybridization, and Association With Outcome.
C. Morrison, M. Radmacher, N. Mohammed, D. Suster, H. Auer, S. Jones, J. Riggenbach, N. Kelbick, G. Bos, and J. Mayerson (2005)
J. Clin. Oncol. 23, 9369-9376
   Abstract »    Full Text »    PDF »
Targeted Destruction of c-Myc by an Engineered Ubiquitin Ligase Suppresses Cell Transformation and Tumor Formation.
S. Hatakeyama, M. Watanabe, Y. Fujii, and K. I. Nakayama (2005)
Cancer Res. 65, 7874-7879
   Abstract »    Full Text »    PDF »
On mammary stem cells.
W. A. Woodward, M. S. Chen, F. Behbod, and J. M. Rosen (2005)
J. Cell Sci. 118, 3585-3594
   Abstract »    Full Text »    PDF »
Repressible transgenic model of NRAS oncogene-driven mast cell disease in the mouse.
S. M. Wiesner, J. M. Jones, D. E. Hasz, and D. A. Largaespada (2005)
Blood 106, 1054-1062
   Abstract »    Full Text »    PDF »
c-Myc induces chromosomal rearrangements through telomere and chromosome remodeling in the interphase nucleus.
S. F. Louis, B. J. Vermolen, Y. Garini, I. T. Young, A. Guffei, Z. Lichtensztejn, F. Kuttler, T. C. Y. Chuang, S. Moshir, V. Mougey, et al. (2005)
PNAS 102, 9613-9618
   Abstract »    Full Text »    PDF »
Molecular Consequences of Silencing Mutant K-ras in Pancreatic Cancer Cells: Justification for K-ras-Directed Therapy.
J. B. Fleming, G.-L. Shen, S. E. Holloway, M. Davis, and R. A. Brekken (2005)
Mol. Cancer Res. 3, 413-423
   Abstract »    Full Text »    PDF »
Inactivation of Myc in Murine Two-Hit B lymphomas Causes Dormancy with Elevated Levels of Interleukin 10 Receptor and CD20: Implications for Adjuvant Therapies.
D. Yu, M. Dews, A. Park, J. W. Tobias, and A. Thomas-Tikhonenko (2005)
Cancer Res. 65, 5454-5461
   Abstract »    Full Text »    PDF »
Tumor Dormancy and MYC Inactivation: Pushing Cancer to the Brink of Normalcy.
C. M. Shachaf and D. W. Felsher (2005)
Cancer Res. 65, 4471-4474
   Abstract »    Full Text »    PDF »
Inactivation of p21WAF1/cip1 Enhances Intestinal Tumor Formation in Muc2-/- Mice.
W. Yang, A. Velcich, I. Lozonschi, J. Liang, C. Nicholas, M. Zhuang, L. Bancroft, and L. H. Augenlicht (2005)
Am. J. Pathol. 166, 1239-1246
   Abstract »    Full Text »    PDF »
Expression Profiling of Human Hepatoma Cells Reveals Global Repression of Genes Involved in Cell Proliferation, Growth, and Apoptosis upon Infection with Parvovirus H-1.
J. Li, E. Werner, M. Hergenhahn, R. Poirey, Z. Luo, J. Rommelaere, and J.-C. Jauniaux (2005)
J. Virol. 79, 2274-2286
   Abstract »    Full Text »    PDF »
Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle.
M. E. Hutchin, M. S.T. Kariapper, M. Grachtchouk, A. Wang, L. Wei, D. Cummings, J. Liu, L. E. Michael, A. Glick, and A. A. Dlugosz (2005)
Genes & Dev. 19, 214-223
   Abstract »    Full Text »    PDF »
Ribavirin suppresses eIF4E-mediated oncogenic transformation by physical mimicry of the 7-methyl guanosine mRNA cap.
A. Kentsis, I. Topisirovic, B. Culjkovic, L. Shao, and K. L. B. Borden (2004)
PNAS 101, 18105-18110
   Abstract »    Full Text »    PDF »
Androgen-Induced Differentiation and Tumorigenicity of Human Prostate Epithelial Cells.
R. Berger, P. G. Febbo, P. K. Majumder, J. J. Zhao, S. Mukherjee, S. Signoretti, K. T. Campbell, W. R. Sellers, T. M. Roberts, M. Loda, et al. (2004)
Cancer Res. 64, 8867-8875
   Abstract »    Full Text »    PDF »
Targeted Knockdown of the RNA-binding Protein CRD-BP Promotes Cell Proliferation via an Insulin-like Growth Factor II-dependent Pathway in Human K562 Leukemia Cells.
B. Liao, M. Patel, Y. Hu, S. Charles, D. J. Herrick, and G. Brewer (2004)
J. Biol. Chem. 279, 48716-48724
   Abstract »    Full Text »    PDF »
c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation.
A. Wilson, M. J. Murphy, T. Oskarsson, K. Kaloulis, M. D. Bettess, G. M. Oser, A.-C. Pasche, C. Knabenhans, H. R. MacDonald, and A. Trumpp (2004)
Genes & Dev. 18, 2747-2763
   Abstract »    Full Text »    PDF »
Mina53 as a Potential Prognostic Factor for Esophageal Squamous Cell Carcinoma.
M. Tsuneoka, H. Fujita, N. Arima, K. Teye, T. Okamura, H. Inutsuka, Y. Koda, K. Shirouzu, and H. Kimura (2004)
Clin. Cancer Res. 10, 7347-7356
   Abstract »    Full Text »    PDF »
Transcriptional control of SV40 T-antigen expression allows a complete reversion of immortalization.
T. May, H. Hauser, and D. Wirth (2004)
Nucleic Acids Res. 32, 5529-5538
   Abstract »    Full Text »    PDF »
Reprogramming of a melanoma genome by nuclear transplantation.
K. Hochedlinger, R. Blelloch, C. Brennan, Y. Yamada, M. Kim, L. Chin, and R. Jaenisch (2004)
Genes & Dev. 18, 1875-1885
   Abstract »    Full Text »    PDF »
Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma.
S. Trudel, S. Ely, Y. Farooqi, M. Affer, D. F. Robbiani, M. Chesi, and P. L. Bergsagel (2004)
Blood 103, 3521-3528
   Abstract »    Full Text »    PDF »
Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue.
C. L. Grand, T. J. Powell, R. B. Nagle, D. J. Bearss, D. Tye, M. Gleason-Guzman, and L. H. Hurley (2004)
PNAS 101, 6140-6145
   Abstract »    Full Text »    PDF »
Increased Expression of a Myc Target Gene Mina53 in Human Colon Cancer.
K. Teye, M. Tsuneoka, N. Arima, Y. Koda, Y. Nakamura, Y. Ueta, K. Shirouzu, and H. Kimura (2004)
Am. J. Pathol. 164, 205-216
   Abstract »    Full Text »    PDF »
Antitumor efficacy of cytotoxic drugs and the monoclonal antibody 806 is enhanced by the EGF receptor inhibitor AG1478.
T. G. Johns, R. B. Luwor, C. Murone, F. Walker, J. Weinstock, A. A. Vitali, R. M. Perera, A. A. Jungbluth, E. Stockert, L. J. Old, et al. (2003)
PNAS 100, 15871-15876
   Abstract »    Full Text »    PDF »
Loss of Protein Phosphatase 2A Expression Correlates with Phosphorylation of DP-1 and Reversal of Dysplasia through Differentiation in a Conditional Mouse Model of Cancer Progression.
M. T. Tilli, S. L. Hudgins, M. S. Frech, E. D. Halama, J.-P. Renou, and P. A. Furth (2003)
Cancer Res. 63, 7668-7673
   Abstract »    Full Text »    PDF »
Molecular Pharmacology of Cancer Therapy in Human Colorectal Cancer by Gene Expression Profiling.
P. A. Clarke, M. L. George, S. Easdale, D. Cunningham, R. I. Swift, M. E. Hill, D. M. Tait, and P. Workman (2003)
Cancer Res. 63, 6855-6863
   Abstract »    Full Text »    PDF »
Effects of MYCN Antisense Oligonucleotide Administration on Tumorigenesis in a Murine Model of Neuroblastoma.
C. A. Burkhart, A. J. Cheng, J. Madafiglio, M. Kavallaris, M. Mili, G. M. Marshall, W. A. Weiss, L. M. Khachigian, M. D. Norris, and M. Haber (2003)
J Natl Cancer Inst 95, 1394-1403
   Abstract »    Full Text »    PDF »
Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression.
A. Karlsson, D. Deb-Basu, A. Cherry, S. Turner, J. Ford, and D. W. Felsher (2003)
PNAS 100, 9974-9979
   Abstract »    Full Text »    PDF »
Regulation of c-myc Gene by Nitric Oxide via Inactivating NF-{kappa}B Complex in P19 Mouse Embryonal Carcinoma Cells.
S. W. Park and L.-N. Wei (2003)
J. Biol. Chem. 278, 29776-29782
   Abstract »    Full Text »    PDF »
A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells.
Z. Li, S. Van Calcar, C. Qu, W. K. Cavenee, M. Q. Zhang, and B. Ren (2003)
PNAS 100, 8164-8169
   Abstract »    Full Text »    PDF »
Application of Gene Expression Profiling to Colon Cell Maturation, Transformation and Chemoprevention.
L. H. Augenlicht, A. Velcich, L. Klampfer, J. Huang, G. Corner, M. Aranes, C. Laboisse, B. Rigas, M. Lipkin, K. Yang, et al. (2003)
J. Nutr. 133, 2410S-2416
   Abstract »    Full Text »    PDF »
Cell context-specific effects of the BCR-ABL oncogene monitored in hematopoietic progenitors.
S. Wong, J. McLaughlin, D. Cheng, and O. N. Witte (2003)
Blood 101, 4088-4097
   Abstract »    Full Text »    PDF »
Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.
A. Danilkovitch-Miagkova, F.-M. Duh, I. Kuzmin, D. Angeloni, S.-L. Liu, A. D. Miller, and M. I. Lerman (2003)
PNAS 100, 4580-4585
   Abstract »    Full Text »    PDF »
Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth.
P. L. Leong, G. A. Andrews, D. E. Johnson, K. F. Dyer, S. Xi, J. C. Mai, P. D. Robbins, S. Gadiparthi, N. A. Burke, S. F. Watkins, et al. (2003)
PNAS 100, 4138-4143
   Abstract »    Full Text »    PDF »
Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations.
A. Karlsson, S. Giuriato, F. Tang, J. Fung-Weier, G. Levan, and D. W. Felsher (2003)
Blood 101, 2797-2803
   Abstract »    Full Text »    PDF »
Oscillation between B-lymphoid and myeloid lineages in Myc-induced hematopoietic tumors following spontaneous silencing/reactivation of the EBF/Pax5 pathway.
D. Yu, D. Allman, M. H. Goldschmidt, M. L. Atchison, J. G. Monroe, and A. Thomas-Tikhonenko (2003)
Blood 101, 1950-1955
   Abstract »    Full Text »    PDF »
Impact of p53 loss on reversal and recurrence of conditional Wnt-induced tumorigenesis.
E. J. Gunther, S. E. Moody, G. K. Belka, K. T. Hahn, N. Innocent, K. D. Dugan, R. D. Cardiff, and L. A. Chodosh (2003)
Genes & Dev. 17, 488-501
   Abstract »    Full Text »    PDF »
Myc-Induced T Cell Leukemia in Transgenic Zebrafish.
D. M. Langenau, D. Traver, A. A. Ferrando, J. L. Kutok, J. C. Aster, J. P. Kanki, S. Lin, E. Prochownik, N. S. Trede, L. I. Zon, et al. (2003)
Science 299, 887-890
   Abstract »    Full Text »    PDF »
p53 Is Required for 1,25-Dihydroxyvitamin D3-Induced G0 Arrest But Is Not Required for G1 Accumulation or Apoptosis of LNCaP Prostate Cancer Cells.
T. C. Polek, L. V. Stewart, E. J. Ryu, M. B. Cohen, E. A. Allegretto, and N. L. Weigel (2003)
Endocrinology 144, 50-60
   Abstract »    Full Text »    PDF »
Myc Recruits P-TEFb to Mediate the Final Step in the Transcriptional Activation of the cad Promoter.
S. R. Eberhardy and P. J. Farnham (2002)
J. Biol. Chem. 277, 40156-40162
   Abstract »    Full Text »    PDF »
c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression.
T. A. Baudino, C. McKay, H. Pendeville-Samain, J. A. Nilsson, K. H. Maclean, E. L. White, A. C. Davis, J. N. Ihle, and J. L. Cleveland (2002)
Genes & Dev. 16, 2530-2543
   Abstract »    Full Text »    PDF »


ADVERTISEMENT
Click Me!

ADVERTISEMENT
Click Me!

To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)