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Endocrinology |
Robert H. Lurie Comprehensive Cancer Center [J. M. S., H. L., V. C. J.] and Department of Surgery [D. J. B.], Northwestern University Medical School, Chicago, Illinois 60611, and Signal Pharmaceuticals, San Diego, California 92121 [J. W. Z.]
The active metabolite of tamoxifen, 4-hydroxytamoxifen (4-OHT), is used
in the laboratory for mechanistic studies of antiestrogen action. This
compound binds to the estrogen receptor 
(ER) and silences
activating function 2 (AF2) in the ligand binding domain, but
activating function 1 (AF1) at the other end of the ER remains
constitutive and is considered to be ligand independent. Amino acid
D351 in the ligand binding domain appears to be critical for
interactions with the antiestrogenic side chain of antiestrogens. We
have devised an assay to evaluate the biological activity of 351 mutant
ERs and antiestrogens at the transforming growth factor
(TGF) gene in situ (J. I. MacGregor
Schafer et al., Cancer Res., 59:
4308–4313, 1999). The substitution of glycine for aspartate at
position 351 results in the conversion of the 4-OHT:ER complex from
estrogen-like to completely antiestrogenic. In cells stably expressing
D351G ER, the ER retains responsiveness to estradiol (E2)
and also retains antiestrogenic responsiveness to both raloxifene and
ICI 182,780. The relative binding affinity of E2 for D351G
ER (0.77 ± 0.17 x 10-9
M) is comparable with wild-type ER (0.42 ± 0.08 x 10-9 M). In addition,
the D351G ER retains the ability to bind SRC-1 in the presence of
E2, thus D351G ER AF2 activity has not been compromised. We
also used a cell line stably expressing an ER with a triple mutation in
helix 12 (D538A, E542A, and D545A) that ablated AF2 activity, which
resulted in decreased effects of E2, suggesting that both
AF1 and AF2 activity are required for maximal estrogen activity in
MDA-MB-231 cells. Interestingly, the triple mutation also completely
reduced the estrogen-like actions of 4-OHT. We propose that a specific
mutation at amino acid 351 can allosterically silence AF1 in the
4-OHT:ER complex by either preventing the binding of coactivators or
encouraging the binding of a corepressor molecule. We suggest that the
4-OHT-specific site responsible for estrogen-like actions can be
referred to as AF2b. This binding site would consist of at least four
carboxylic acids at amino acids 351 and 538, 542 and 545 in helix 12 to
permit coactivator docking for gene activation. The AF2b site is
distinct from AF2 for E2 action. Further studies will
provide insight into the estrogen-like actions of tamoxifen in select
tissues and breast tumors and identify a significant mechanism of drug
resistance to tamoxifen.
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