Premium
Estrogen Mediation of Breast Tumor Formation Involves Estrogen Receptor‐Dependent, as Well as Independent, Genotoxic Effects
Author(s) -
Santen Richard,
Cavalieri Ercole,
Rogan Eleanor,
Russo Jose,
Guttenplan Joseph,
Ingle James,
Yue Wei
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2008.03685.x
Subject(s) - estrogen , estrogen receptor , mediation , estrogen receptor beta , medicine , tamoxifen , gper , endocrinology , estrogen receptor alpha , selective estrogen receptor modulator , cancer research , chemistry , breast cancer , cancer , political science , law
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.