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

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.

journal_name

Ann N Y Acad Sci

journal_title

Annals of the New York Academy of Sciences

authors

Santen R,Cavalieri E,Rogan E,Russo J,Guttenplan J,Ingle J,Yue W

doi

10.1111/j.1749-6632.2008.03685.x

subject

Has Abstract

pub_date

2009-02-01 00:00:00

pages

132-40

eissn

0077-8923

issn

1749-6632

pii

NYAS03685

journal_volume

1155

pub_type

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