Estrogen mediation of breast tumor formation involves estrogen receptor-dependent, as well as independent, genotoxic effects

Richard Santen, Ercole Cavalieri, Eleanor Rogan, Jose Russo, Joseph Guttenplan, James Ingle, Wei Yue

Research output: Chapter in Book/Report/Conference proceedingConference contribution

62 Scopus citations

Abstract

Long-term exposure to estrogens influences the development of breast cancer in women, but the precise mechanisms involved are not clearly defined. Our working hypothesis is that estrogen modulates this process by two separate processes. One involves the binding of estradiol to estrogen receptor (ER) alpha with stimulation of cell proliferation. Errors in DNA occurring during replication result in fixed mutations when not repaired. The other process results from the formation of genotoxic metabolites of estradiol, which can bind to DNA, cause depurination, and result in mutations. Our collaborative group, funded by a Department of Defense Center of Excellence grant, has examined this hypothesis using a variety of experimental methods. Estradiol and its catechol-estrogen metabolite 4-OH-estradiol causes mutations in cell culture systems and can transform benign MCF-10F cells, allowing them to cause tumors in SCID mice. We have demonstrated loss of heterozygosity and gains and losses of DNA segments by comparative genomic hybridization methodology. The depurinated estradiol-guanine and -adenine adducts are measurable in MCF-7 breast cancer cells in culture and in mouse mammary tissue. The double transgenic, alpha estrogen receptor knockout/Wnt-1 knockin mouse model allows us to dissect out the separate effects of ER-mediated and ER-independent actions of estradiol. Knock out of the ER alpha delays the onset of breast tumors in this model, demonstrating a role of receptor-mediated actions. Oophorectomy delays the onset of tumors and reduces overall incidence, providing evidence for an ER-independent effect. Taken together, these data suggest that both ER-dependent and genotoxic ER-independent effects of estradiol mediate breast cancer development.

Original languageEnglish (US)
Title of host publicationSteroid Enzymes and Cancer
PublisherBlackwell Publishing Inc.
Pages132-140
Number of pages9
ISBN (Print)9781573317450
DOIs
StatePublished - Feb 2009

Publication series

NameAnnals of the New York Academy of Sciences
Volume1155
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • 4-OH-estradiol
  • Breast cancer
  • Estrogen
  • Genotoxicity

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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