Mechanisms of hormonal prevention of breast cancer

Ann N Y Acad Sci. 2001 Dec;952:23-35. doi: 10.1111/j.1749-6632.2001.tb02725.x.


Reproductive history is a consistent risk factor for human breast cancer. Epidemiological studies have repeatedly demonstrated that early age of first pregnancy is a strong protective factor against breast cancer and provides a physiologically operative model to achieve a practical mode of prevention. In rodents, the effects of full-term pregnancy can be mimicked by a three-week exposure to low doses of estrogen and progesterone. Neither hormone alone is sufficient to induce protection. The cellular and molecular mechanisms that underlie hormone-induced refractoriness are largely unresolved. Our recent studies have demonstrated that an early cellular response that is altered in hormone-treated mammary cells is the initial proliferative burst induced by the chemical carcinogen methylnitrosourea. The decrease in proliferation is also accompanied by a decrease in the ability of estrogen receptor-positive cells to proliferate. RNA expression of several mammary cell-cycle-related genes is not altered in hormone-treated mice; however, immunohistochemical assays demonstrate that the protein level and nuclear compartmentalization of the p53 tumor suppressor gene are markedly upregulated as a consequence of hormone treatment. These results support the hypothesis that hormone stimulation, at a critical period in mammary development, results in cells with persistent changes in the intracellular regulatory loops governing proliferation and response to DNA damage. A corollary to this hypothesis is that the genes affected by estrogen and progesterone are independent of alveolar differentiation-specific genes. Suppressive subtractive hybridization-PCR methods have identified several genes that are differentially expressed as a consequence of prior estrogen and progesterone treatment. Future experiments are aimed at determining the mechanisms of hormone-induced upregulation of p53 protein expression as part of the overall goal of identifying and functionally characterizing the genes responsible for the refractory phenotype.

Publication types

  • Review

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Adenocarcinoma / epidemiology
  • Adenocarcinoma / genetics
  • Adenocarcinoma / prevention & control
  • Animals
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / prevention & control*
  • Cell Division
  • DNA Damage
  • Estradiol / administration & dosage
  • Estradiol / therapeutic use*
  • Estrogens / physiology
  • Female
  • Gene Expression Profiling
  • Genes, p53
  • Humans
  • Mammary Glands, Animal / drug effects
  • Mammary Neoplasms, Experimental / chemically induced
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / prevention & control
  • Methylnitrosourea
  • Mice
  • Mice, Inbred Strains
  • Neoplasms, Hormone-Dependent / epidemiology
  • Neoplasms, Hormone-Dependent / prevention & control
  • Pregnancy
  • Progesterone / administration & dosage
  • Progesterone / physiology
  • Progesterone / therapeutic use*
  • Rats
  • Rats, Inbred WF
  • Rats, Sprague-Dawley
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / drug effects
  • Receptors, Progesterone / metabolism
  • Reproductive History
  • Risk Factors


  • Estrogens
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Progesterone
  • Estradiol
  • 9,10-Dimethyl-1,2-benzanthracene
  • Methylnitrosourea