Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Chemoprevention: an essential approach to controlling cancer

Nature Reviews Cancer volume 2, pages 537–543 (2002)Cite this article

Abstract

Mortality that results from the common forms of cancer is still unacceptably high. Despite immense advances in the understanding of the mechanisms of carcinogenesis, in bringing potent new drugs to the clinic and in treating several relatively rare forms of cancer, overall mortality statistics are unlikely to change in a fundamental way until there has been a re-orientation of emphasis in cancer research that will direct greater resources towards prevention of new disease, rather than treatment of end-stage disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The TGF-β signalling pathway represents a new target for potential development of new drugs for chemoprevention.
Figure 2: A standard study design for evaluating a new chemopreventive agent.
Figure 3: Extension of the latency period is important for chemoprevention in both animals and humans.

Similar content being viewed by others

References

  1. Sporn, M. B. Carcinogenesis and cancer: different perspectives on the same disease. Cancer Res. 51, 6215–6218 (1991).

    CAS  PubMed  Google Scholar 

  2. Chemoprevention Working Group. Prevention of cancer in the next millennium: report of the Chemoprevention Working Group to the American Association for Cancer Research. Cancer Res. 59, 4743–4758 (1999).

  3. O'Shaughnessy, J. A. et al. Treatment and prevention of intraepithelial neoplasia: an important target for accelerated new agent development. Clin. Cancer Res. 8, 314–346 (2002).

    PubMed  Google Scholar 

  4. Lippman, S. M. & Hong, W. K. Cancer prevention by delay. Clin. Cancer Res. 8, 305–313 (2002).

    PubMed  Google Scholar 

  5. The Oxford English Dictionary 2nd edn Vol. XII p. 444 (Clarendon Press, Oxford, 1989).

  6. Pierce, G. B., Shikes, R. & Fink, L. M. Cancer: A Problem of Developmental Biology (Prentice Hall, Englewood Cliffs, New Jersey, 1978).

    Google Scholar 

  7. Mintz, B. & Fleischman, R. A. Teratocarcinomas and other neoplasms as developmental defects in gene expression. Adv. Cancer Res. 34, 211–278 (1981).

    Article  CAS  Google Scholar 

  8. Brivanlou, A. H. & Darnell, J. E. Jr. Signal transduction and the control of gene expression. Science 295, 813–818 (2002).

    Article  CAS  Google Scholar 

  9. Baylin, S. B., Herman, J. G., Graff, J. R., Vertino, P. M. & Issa, J. P. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv. Cancer Res. 72, 141–196 (1998).

    Article  CAS  Google Scholar 

  10. Robertson, K. D. & Jones, P. A. DNA methylation: past, present and future directions. Carcinogenesis 21, 461–467 (2000).

    Article  CAS  Google Scholar 

  11. Marks, P. A. et al. Histone deacetylases and cancer: causes and therapies. Nature Rev. Cancer 1, 194–202 (2001).

    Article  CAS  Google Scholar 

  12. Clark, W. H. Jr. The nature of cancer: morphogenesis and progressive (self)-disorganization in neoplastic development and progression. Acta Oncologica 34, 3–21 (1995).

    Article  Google Scholar 

  13. Bissell, M. J. & Radisky, D. Putting tumors in context. Nature Rev. Cancer 1, 46–54 (2001).

    Article  CAS  Google Scholar 

  14. Liotta, L. A. & Kohn, E. C. The microenvironment of the tumor–host interface. Nature 411, 375–379 (2001).

    Article  CAS  Google Scholar 

  15. Hennekens, C. H. et al. Lack of effect of long-term supplementation with β-carotene on the incidence of malignant neoplasms and cardiovascular disease. N. Engl. J. Med. 334, 1145–1149 (1996).

    Article  CAS  Google Scholar 

  16. Omenn, G. S. et al. Effects of a combination of β-carotene and vitamin A on lung cancer and cardiovascular disease. N. Engl. J. Med. 334, 1150–1155 (1996).

    Article  CAS  Google Scholar 

  17. Kelloff, G. J. Perspectives on cancer chemoprevention research and drug development. Adv. Cancer Res. 78, 199–334 (2000).

    Article  CAS  Google Scholar 

  18. Mangelsdorf, D. J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 (1995).

    Article  CAS  Google Scholar 

  19. Katzenellenbogen, B. S. & Katzenellenbogen, J. A. Defining the 'S' in SERMs. Science 295, 2380–2381 (2002).

    Article  CAS  Google Scholar 

  20. Fisher, B. et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J. Natl Cancer Inst. 90, 1371–1388 (1998).

    Article  CAS  Google Scholar 

  21. Jordan, V. C. & Morrow, M. Tamoxifen, raloxifene, and the prevention of breast cancer. Endocr. Rev. 20, 253–278 (1999).

    CAS  PubMed  Google Scholar 

  22. Sporn, M. B., Suh, N. & Mangelsdorf, D. J. Prospects for prevention and treatment of cancer with selective PPAR-γ modulators (SPARMs). Trends Mol. Med. 7, 395–400 (2001).

    Article  CAS  Google Scholar 

  23. Cauley, J. A. et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene. 4-year results from the MORE trial. Multiple outcomes of raloxifene evalutaion. Breast Cancer Res. Treat. 65, 125–134 (2001).

    Article  CAS  Google Scholar 

  24. Suh, N. et al. Arzoxifene, a new selective estrogen receptor modulator for chemoprevention of experimental breast cancer. Cancer Res. 61, 8412–8415 (2001).

    CAS  PubMed  Google Scholar 

  25. Horvath, L. G. et al. Frequent loss of estrogen receptor-β expression in prostate cancer. Cancer Res. 61, 5331–5335 (2001).

    CAS  PubMed  Google Scholar 

  26. Lucia, M. S. et al. Chemopreventive activity of tamoxifen, N-(4-hydroxyphenyl)-retinamide, and the vitamin D analogue Ro24-5531 for androgen-promoted carcinomas of the rat seminal vesicle and prostate. Cancer Res. 55, 5621–5627 (1995).

    CAS  PubMed  Google Scholar 

  27. Campbell-Thompson, M., Lynch, I. J. & Bhardwaj, B. Expression of estrogen receptor (ER) subtypes and ERβ isoforms in colon cancer. Cancer Res. 61, 632–640 (2001).

    CAS  PubMed  Google Scholar 

  28. Chawla, A., Repa, J. J., Evans, R. M. & Mangelsdorf, D. J. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870 (2001).

    Article  CAS  Google Scholar 

  29. Bischoff, E. D., Gottardis, M. M., Moon, T. E., Heyman, R. A. & Lamph, W. W. Beyond tamoxifen: the retinoid X receptor-selective ligand LGD1069 (TARGRETIN) causes complete regression of mammary carcinoma. Cancer Res. 58, 479–484 (1998).

    CAS  PubMed  Google Scholar 

  30. Wu, K. et al. Suppression of mammary tumorigenesis in transgenic mice by the RXR-selective retinoid, LGD1069. Cancer Epidemiol. Biomarkers Prev. 11, 467–474 (2002).

    CAS  PubMed  Google Scholar 

  31. Jones, G., Strugnell, S. A. & DeLuca, H. F. Current understanding of the molecular actions of vitamin D. Physiol. Rev. 78, 1193–1231 (1998).

    Article  CAS  Google Scholar 

  32. Guyton, K. Z., Kensler, T. W. & Posner, G. H. Cancer chemoprevention using natural vitamin D and synthetic analogs. Annu. Rev. Pharmacol. Toxicol. 41, 421–442 (2001).

    Article  CAS  Google Scholar 

  33. Martinez, M. E. & Willett, N. S. Calcium, vitamin D, and colorectal cancer: a review of the epidemiologic evidence. Cancer Epidemiol. Biomarkers Prev. 7, 163–168 (1998).

    CAS  PubMed  Google Scholar 

  34. Makishima, M. et al. Vitamin D receptor as a bile acid sensor that detoxifies the colon carcinogen lithocholic acid. Science 296, 1313–1316 (2002).

    Article  CAS  Google Scholar 

  35. Yanagisawa, J. et al. Convergence of transforming growth factor-β and vitamin D signaling pathways on SMAD transcriptional coactivators. Science 283, 1317–1321 (1999).

    Article  CAS  Google Scholar 

  36. Misteli, T. Protein dynamics: implications for nuclear architecture and gene expression. Science 291, 843–847 (2001).

    Article  CAS  Google Scholar 

  37. Reddy, B. S. et al. Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res. 60, 293–297 (2000).

    CAS  PubMed  Google Scholar 

  38. Steinbach, G. et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N. Engl. J. Med. 342, 1946–1952 (2000).

    Article  CAS  Google Scholar 

  39. Gupta, R. A. & DuBois, R. N. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nature Rev. Cancer 1, 11–21 (2001).

    Article  CAS  Google Scholar 

  40. Bharti, A. C. & Aggarwal, B. B. Nuclear factor κB and cancer: its role in prevention and therapy. Biochem. Pharmacol (in the press).

  41. Cameron, E. E., Bachman, K. E., Myohanen, S., Herman, J. G. & Baylin, S. B. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nature Genet. 21, 103–107 (1999).

    Article  CAS  Google Scholar 

  42. Lantry, L. E. et al. 5-Aza-2′-deoxycytidine is chemopreventive in a 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone-induced primary mouse lung tumor model. Carcinogenesis 20, 343–346 (1999).

    Article  CAS  Google Scholar 

  43. Ferrara, F. F. et al. Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res. 61, 2–7 (2001).

    PubMed  Google Scholar 

  44. Widschwendter, M. et al. Methylation and silencing of the retinoic acid receptor-β2 gene in breast cancer. J. Natl Cancer Inst. 92, 826–832 (2000).

    Article  CAS  Google Scholar 

  45. Tang, B. et al. Transforming growth factor-β1 is a new form of tumor suppressor with true haploid insufficiency. Nature Med. 4, 802–807 (1998).

    Article  CAS  Google Scholar 

  46. Massagué, J., Blain, S. W. & Lo, R. S. TGF-β signaling in growth control, cancer, and heritable disorders. Cell 103, 295–309 (2000).

    Article  Google Scholar 

  47. De Caestecker, M. P., Piek, E. & Roberts, A. B. Role of transforming growth factor-β signaling in cancer. J. Natl Cancer Inst. 92, 1388–1402 (2000).

    Article  CAS  Google Scholar 

  48. Derynck, R., Akhurst, R. J. & Balmain, A. TGF-β signaling in tumor suppression and cancer progression. Nature Genet. 29, 117–129 (2001).

    Article  CAS  Google Scholar 

  49. Kim, S. J., Im, Y. H., Markowitz, S. D. & Bang, Y. J. Molecular mechanisms of inactivation of TGF-β receptors during carcinogenesis. Cytokine Growth Factor Rev. 11, 159–168 (2000).

    Article  CAS  Google Scholar 

  50. Chen, T. et al. Transforming growth factor-β receptor type I gene is frequently mutated in ovarian carcinomas. Cancer Res. 61, 4679–4682 (2001).

    CAS  PubMed  Google Scholar 

  51. Fiocchi, C. TGF-β/Smad signaling defects in inflammatory bowel disease: mechanisms and possible novel therapies for chronic inflammation. J. Clin. Invest. 108, 523–526 (2001).

    Article  CAS  Google Scholar 

  52. Monteleone, G. et al. Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J. Clin. Invest. 108, 601–609 (2001).

    Article  CAS  Google Scholar 

  53. Danielsen, A. J. & Maihle, N. J. The EGF/ErbB receptor family and apoptosis. Growth Factors 20, 1–15 (2002).

    Article  CAS  Google Scholar 

  54. Raben, D., Helfrich, B. A., Chan, D., Johnson, G. & Bunn, P. A. Jr. ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. Semin. Oncol. 29, S37–S46 (2002).

    Article  Google Scholar 

  55. Karin, M., Cao, Y., Greten, F. R. & Li, Z. W. NF-κB in cancer: from innocent bystander to major culprit. Nature Rev Cancer 2, 301–310 (2002). | PubMed|

    Article  CAS  Google Scholar 

  56. Bromberg, J. & Darnell, J. E. The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468–2473 (2000).

    Article  CAS  Google Scholar 

  57. Turkson, J. & Jove, R. STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19, 6613–6626 (2000).

    Article  CAS  Google Scholar 

  58. Malumbres, M. & Barbacid, M. To cycle or not to cycle: a critical decision in cancer. Nature Rev. Cancer 1, 222–231 (2001).

    Article  CAS  Google Scholar 

  59. Teicher, B. A. (ed.) Tumor Models in Cancer Research. 690 (Humana, Totowa, New Jersey, 2002).

    Google Scholar 

  60. Hong, W. K., Lippman, S. M., Hittleman, W. N. & Lotan, R. Retinoid chemoprevention of aerodigestive cancer: from basic research to the clinic. Clin. Cancer Res. 1, 677–686 (1995).

    Google Scholar 

  61. Sporn, M. B. Hobson's choice and the need for combinations of new agents for the prevention and treatment of breast cancer. J. Natl Cancer Inst. 94, 242–243 (2002).

    Article  Google Scholar 

  62. Song, C. Z., Tian, X. & Gelehrter, T. D. Glucocorticoid receptor inhibits transforming growth factor-β signaling by directly targeting the transcriptional activation function of Smad3. Proc. Natl Acad. Sci. 96, 11776–11781 (1999).

    Article  CAS  Google Scholar 

  63. Matsuda, T., Yamamoto, T., Muraguchi, A. & Saatcioglu, F. Cross-talk between transforming growth factor-β and estrogen receptor signaling through Smad3. J. Biol. Chem. 276, 42908–42914 (2001).

    Article  CAS  Google Scholar 

  64. Chipuk, J. E. et al. The androgen receptor represses transforming growth factor-β signaling through interaction with Smad3. J. Biol. Chem. 277, 1240–1248 (2002).

    Article  CAS  Google Scholar 

  65. Kang, H. Y. et al. From transforming growth factor-β signaling to androgen action: identification of Smad3 as an androgen receptor coregulator in prostate cancer cells. Proc. Natl Acad. Sci. 98, 3018–3023 (2001).

    Article  CAS  Google Scholar 

  66. Fu, M. et al. Peroxisome proliferator-activated receptor-γ inhibits transforming growth factor-β-induced connective tissue growth factor expression in human aortic smooth muscle cells by interfering with Smad3. J. Biol. Chem. 276, 45888–45894 (2001).

    Article  CAS  Google Scholar 

  67. Ulloa, L., Doody, J. & Massague, J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-γ/STAT pathway. Nature 397, 710–713 (1999).

    Article  CAS  Google Scholar 

  68. Bitzer, M. et al. A mechanism of suppression of TGF-β/SMAD signaling by NF-κB/RelA. Genes Dev. 14, 187–197 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. American Cancer Society. Estimated Cancer Deaths and New Cases by Sex and Site: 1971 Cancer Facts and Figures (American Cancer Society, New York, 1970).

  70. Jemal, A., Thomas, A., Murray, T. & Thun, M. Cancer Statistics 2002. CA Cancer J. Clin. 52, 23–47 2002).

Download references

Acknowledgements

We thank M. Padgett for expert assistance in the preparation of the manuscript. Our research is supported by grants from the National Cancer Institute, the Department of Defense, the National Foundation for Cancer Research, and the Oliver and Jennie Donaldson Trust. M. B. S is an Oscar M. Cohn Professor.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Dartmouth Medical School, Hanover, 03755, New Hampshire, USA

    Michael B. Sporn & Nanjoo Suh

Authors
  1. Michael B. Sporn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nanjoo Suh
    View author publications

    You can also search for this author in PubMed Google Scholar

Related links

Related links

DATABASES

Cancer.gov

breast cancer

chronic myelogenous leukaemia

colon cancer

endometrial cancer

gastric cancer

head and neck cancer

Hodgkin's disease

lung cancer

ovarian cancer

pancreatic cancer

prostate cancer

testicular cancer

LocusLink

androgen receptor

BRCA1

BRCA2

COX1

COX2

EGF

ERBB2

ERα

ERβ

IFN-γ

IL-1α

NF-κB

PPARγ

RARα

RARβ

RARγ

RXRα

RXRβ

RXRγ

SMAD2

SMAD3

SMAD4

SMAD6

SMAD7

STAT1

TGF-β

TNF-α

VDR

Medscape DrugInfo

celecoxib

Gleevec

Herceptin

raloxifene

tamoxifen

OMIM

familial adenomatous polyposis

inflammatory bowel disease

osteoporosis

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sporn, M., Suh, N. Chemoprevention: an essential approach to controlling cancer. Nat Rev Cancer 2, 537–543 (2002). https://doi.org/10.1038/nrc844

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc844

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing