Erschienen in:
01.07.2010 | Preclinical study
A hypersensitive estrogen receptor α mutation that alters dynamic protein interactions
verfasst von:
Matthew H. Herynk, Torsten Hopp, Yukun Cui, Airu Niu, Arnoldo Corona-Rodriguez, Suzanne A. W. Fuqua
Erschienen in:
Breast Cancer Research and Treatment
|
Ausgabe 2/2010
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Abstract
Estrogen receptor α (ERα) is highly regulated through multiple mechanisms including cell signaling, posttranslational modifications, and protein–protein interactions. We have previously identified a K303R ERα mutation within the hinge region of ERα. This mutation results in an altered posttranslational regulation and increased in vitro growth in the presence of low estrogen concentrations. We sought to determine if cells expressing this mutant ERα would display hypersensitive tumor growth in in vivo athymic ovariectomized nude mice. MCF-7 cells, stably expressing the K303R ERα, formed tumors in nude mice faster than cells expressing wild-type ERα in the presence of low levels of estrogen. When estrogen was withdrawn, all tumors regressed but half of the K303R ERα-expressing tumors became estrogen-independent and regrew. We evaluated potential mechanisms for the observed hypersensitivity. The mutant ERα did not demonstrate increased estrogen binding affinity, but did exhibit increased interactions with members of the SRC family of coactivators. The mutant ERα demonstrated increased levels and occupancy time on the pS2 promoter. In the presence of the K303R ERα, the SRC-3 and p300 coactivators also displayed increased levels and time on the pS2 promoter. The K303R ERα has, in part, lost critical negative regulation by the F domain. Collectively, these data demonstrate an important role for the K303R ERα mutation in hormonal regulation of tumor growth and estrogen-regulated promoter dynamics in human breast cancer.