Dual role of oestrogens as hormones and pro-carcinogens: tumour initiation by metabolic activation of oestrogens

Eur J Cancer Prev. 1997 Feb;6(1):3-10. doi: 10.1097/00008469-199702000-00002.


Epidemiological evidence increasingly points to exogenous or endogenous oestrogens as a risk factor for breast cancer. However, it is unlikely that induction of oestrogen-dependent tumour growth is the sole contribution of oestrogens to tumour development in the mammary gland, because oestrogen receptors are barely detectable in normal mammary epithelial cells. In this review, I examine a mechanism for mammary carcinogenesis, which emphasizes tumour initiation by metabolic activation of oestrogens in combination with cell transformation and growth stimulation by oestrogen receptor-mediated processes. Catecholestrogen metabolites are capable of metabolic redox cycling between quinone and hydroquinone forms, a mechanism of free radical generation. Several types of direct and indirect free radical-mediated DNA damage are induced by oestrogens in vitro and in vivo, such as DNA single strand breaks, 8-hydroxylation of guanine bases, and DNA adduct formation by malondialdehyde, a decomposition product of free radical-induced lipid peroxides. The substrate for redox cycling and free radical generation may be 4-hydroxoestradiol, because this metabolite is formed from oestradiol by a specific oestrogen 4-hydroxylase detected in several human organs including mammary tissue. It has also been formed in organs of rodents where oestrogens induce tumours, with the exception of the liver. 4-Hydroxyoestradiol is a potent, long-acting oestrogen and may complete the carcinogenic process by stimulating receptor-mediated proliferation. An understanding of a possible mechanism of mammary carcinogenesis as a result of oestrogen-mediated initiation means that several prevention strategies, based on inhibiting metabolic activation of oestrogens or free radical action, can be developed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Biotransformation
  • Breast Neoplasms / etiology*
  • Breast Neoplasms / prevention & control
  • Carcinogens / metabolism*
  • DNA Damage
  • Estrogens, Conjugated (USP) / adverse effects*
  • Estrogens, Conjugated (USP) / metabolism*
  • Female
  • Free Radicals / adverse effects
  • Free Radicals / metabolism
  • Humans
  • Mammary Neoplasms, Animal / etiology*
  • Mammary Neoplasms, Animal / physiopathology
  • Risk Assessment


  • Carcinogens
  • Estrogens, Conjugated (USP)
  • Free Radicals