Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism

Mutat Res. 2003 Sep;544(1):9-41. doi: 10.1016/s1383-5742(03)00016-4.

Abstract

The major known risk factors for female breast cancer are associated with prolonged exposure to increased levels of oestrogen. The predominant theory relates to effects of oestrogen on cell growth. Enhanced cell proliferation, induced either by endogenous or exogenous oestrogens, increases the number of cell divisions and thereby the possibility for mutation. However, current evidence also supports a role for oxidative metabolites, in particular catechol oestrogens, in the initiation of breast cancer. As observed in drug and chemical metabolism, there is considerable interindividual variability (polymorphism) in the conjugation pathways of both oestrogen and catechol oestrogens. These person-to-person differences, which are attributed to polymorphisms in the genes encoding for the respective enzymes, might define subpopulations of women with higher lifetime exposure to hormone-dependent growth promotion, or to cellular damage from particular oestrogens and/or oestrogen metabolites. Such variation could explain a portion of the cancer susceptibility associated with reproductive effects and hormone exposure. In this paper the potential role of polymorphic genes encoding for enzymes involved in oestrogen biosynthesis (CYP17, CYP19, and 17beta-HSD) and conversion of the oestrogen metabolites and their by-products (COMT, CYP1A1, CYP1B1, GSTM1, GSTM3, GSTP1, GSTT1 and MnSOD) in modulating individual susceptibility to breast cancer are reviewed. Although some of these low-penetrance genes appeared as good candidates for risk factors in the etiology of sporadic breast cancer, better designed and considerably larger studies than the majority of the studies conducted so far are evidently needed before any firm conclusions can be drawn.

Publication types

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

MeSH terms

  • 17-Hydroxysteroid Dehydrogenases / genetics
  • Animals
  • Aromatase / genetics
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Body Constitution
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Cytochrome P-450 CYP1A1 / genetics
  • Cytochrome P-450 CYP1B1
  • Enoyl-CoA Hydratase*
  • Estrogens / biosynthesis
  • Estrogens / metabolism*
  • Female
  • Genetic Predisposition to Disease
  • Glutathione Transferase / genetics
  • Humans
  • Hydro-Lyases
  • Multienzyme Complexes*
  • Peroxisomal Multifunctional Protein-2
  • Polymorphism, Genetic*
  • Reproductive History
  • Smoking
  • Steroid 17-alpha-Hydroxylase / genetics
  • Superoxide Dismutase / genetics

Substances

  • Estrogens
  • Multienzyme Complexes
  • 17-Hydroxysteroid Dehydrogenases
  • Aromatase
  • Aryl Hydrocarbon Hydroxylases
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1B1
  • Steroid 17-alpha-Hydroxylase
  • Superoxide Dismutase
  • Glutathione Transferase
  • Hydro-Lyases
  • Peroxisomal Multifunctional Protein-2
  • HSD17B4 protein, human
  • Enoyl-CoA Hydratase