Chemoprevention of breast cancer by tamoxifen: Risks and opportunities

L. L. Smith, K. Brown, P. Carthew, C. K. Lim, E. A. Martin, J. Styles, I. N.H. White

Research output: Contribution to journalReview articlepeer-review

71 Scopus citations

Abstract

The antiestrogen tamoxifen is widely used in the adjuvant therapy of breast cancers in women and helps to prevent the occurrence of breast tumors in healthy women. However, epidemiological studies have shown tamoxifen treatment to be associated with a 2- to 5-fold increased risk of endometrial cancer. In rats but not in mice, long-term administration of tamoxifen results in an increase in hepatocellular carcinomas. Mechanistically, this occurs through metabolic activation of the drug, mainly by the CYP3A family, to an electrophilic species, that causes DNA damage in target tissues, and subsequently leads to gene mutations. It is controversial whether low levels of DNA damage occur in human uterine tissues, and there is no evidence that this can be causally related to the mechanisms of carcinogenesis. In healthy women, the risk:benefits for the use of tamoxifen is in part related to the risk of developing breast cancer. The results from the carcinogenicity studies in rats do not predict the likelihood that women will develop liver cancer or indeed cancers in other organs. The mechanism of endometrial cancer in women remains unresolved, but the experience with tamoxifen has highlighted the potential problems that need to be addressed in the assessment of future generations of selective estrogen receptor modulators.

Original languageEnglish
Pages (from-to)571-594
Number of pages24
JournalCritical Reviews in Toxicology
Volume30
Issue number5
DOIs
StatePublished - 2000
Externally publishedYes

Keywords

  • Accelerator mass spectrometry
  • Active metabolites
  • DNA damage
  • Liver tumors
  • P-postlabeling
  • Tamoxifen

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