Estrogen receptor-dependent and independent mechanisms of breast cancer carcinogenesis

Wei Yue, James D. Yager, Ji Ping Wang, Eldon R. Jupe, Richard J. Santen

Research output: Contribution to journalReview articlepeer-review

Abstract

Long term exposure to estrogens is associated with an increased risk of breast cancer. The precise mechanisms responsible for estrogen mediated carcinogenesis are not well understood. The most widely accepted theory holds that estradiol (E2), acting through estrogen receptor alpha (ERα), stimulates cell proliferation and initiates mutations arising from replicative errors occurring during pre-mitotic DNA synthesis. The promotional effects of E2 then support the growth of cells harboring mutations. Over a period of time, sufficient numbers of mutations accumulate to induce neoplastic transformation. Laboratory and epidemiological data also suggest that non-receptor mediated mechanisms resulting from the genotoxic effects of estrogen metabolites are involved in breast cancer development. This manuscript critically reviews existing data implicating both ER-dependent and -independent mechanisms. The weight of evidence supports the possibility that both mechanisms are involved in the carcinogenic process. In addition, estrogen metabolites likely modulate stem cell functionality and cancer progression. The roles of ER dependent and independent actions in the carcinogenic process are pertinent to the consideration of breast cancer preventative agents as anti-estrogens block only receptor mediated pathways whereas the aromatase inhibitors block both.

Original languageEnglish (US)
Pages (from-to)161-170
Number of pages10
JournalSteroids
Volume78
Issue number2
DOIs
StatePublished - Feb 1 2013

Keywords

  • Breast cancer
  • Catechol estrogen depurinating adduct
  • Catechol estrogens
  • Estrogen receptor
  • Estrogens
  • Genotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry

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