Tamoxifen versus aromatase inhibitors for breast cancer prevention.
Long-term exposure to estradiol is associated with an increased risk of breast cancer, but the mechanisms responsible are not firmly established. The prevailing theory postulates that estrogens increase the rate of cell proliferation by stimulating estrogen receptor (ER)-mediated transcription, thereby increasing the number of errors occurring during DNA replication. An alternative theory suggests that estradiol is metabolized to quinone derivatives, which directly remove base pairs from DNA through a process called depurination. Error-prone DNA repair then results in point mutations. We postulate that both processes act in an additive or synergistic fashion. If correct, aromatase inhibitors would block both processes, whereas antiestrogens would only inhibit receptor-mediated effects. Accordingly, aromatase inhibitors would be more effective in preventing breast cancer than antiestrogens. Our initial studies showed that catechol-estrogen metabolites are formed in MCF-7 human breast cancer cells in culture. We then used an animal model that allows dissociation of ER-mediated function from the effects of estradiol metabolites and showed formation of genotoxic estradiol metabolites. We also examined the incidence of tumors formed in these ERalpha knockout mice bearing the Wnt-1 transgene. The absence of estradiol markedly reduced the incidence of tumors and delayed their onset. In aggregate, our results support the concept that metabolites of estradiol may act in concert with ER-mediated mechanisms to induce breast cancer. These findings support the possibility that aromatase inhibitors might be more effective than antiestrogens in preventing breast cancer.
Yue
Wei
W
University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Wang
Ji-Ping
JP
Li
Yuebai
Y
Bocchinfuso
Wayne P
WP
Korach
Kenneth S
KS
Devanesan
Prabu D
PD
Rogan
Eleanor
E
Cavalieri
Ercole
E
Santen
Richard J
RJ
D000818:Animals; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000517:prevention & control*; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D013629:Tamoxifen / Q000627:therapeutic use*
D047072:Aromatase Inhibitors; D004965:Estrogen Antagonists; D013629:Tamoxifen