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This version published online on March 19, 2003
Endocrinology, doi:10.1210/en.2002-0027
A more recent version of this article appeared on July 1, 2003
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Submitted on November 11, 2002
Accepted on March 6, 2003

The naturally occurring variant of estrogen receptor ER{Delta}E7 suppresses estrogen-dependent transcriptional activation by both wild-type ER{alpha} and ER{beta}

Juana M. García Pedrero1, Pedro Zuazua1, Carlos Martínez-Campa1, Pedro S. Lazo1, and Sofía Ramos1*

1 Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología Principado de Asturias, Universidad de Oviedo, 33071 Oviedo, Spain.

* To whom correspondence should be addressed. E-mail: sramos{at}correo.uniovi.es.

We have isolated and functionally characterized the exon 7-skipped variant (ER{Delta}E7) of estrogen receptor {alpha} (ER{alpha}), which has emerged as the predominant variant expressed in multiple normal and tumoral tissues. However, to date no function has been established for this variant in mammalian cells. ER{Delta}E7 exhibits a negligible ability to bind ligands, insensitivity to allosteric modulation by estrogen and antiestrogens and loss of estrogen-dependent interaction with p160 coactivators such as SRC-1 and AIB1. ER{Delta}E7 is able to form heterodimers with both ER{alpha} and ER{beta} in a ligand-independent manner. Transient expression experiments in HeLa cells show that increasing amounts of ER{Delta}E7 result in a progressive inhibition of the E2-dependent transcriptional activation by both wild-type ER{alpha} and ER{beta} on ERE-driven promoters. The inhibitory effect of ER{Delta}E7 is due to the inhibition of binding of wild-type receptors to their responsive elements. Surprisingly, the AF1-dependent transactivation triggered by EGF and PMA is also abolished in ER{Delta}E7 despite AF1 integrity, suggesting a cross-talk between AF1 and AF2 regions of the receptor. These results indicate that the naturally occurring variant ER{Delta}E7 is a dominant negative receptor that when expressed at high levels relative to wild-type ERs might have profound effects on several estrogen-dependent functions.
Key words: Estrogen receptor • variant • dominant negative • breast cancer • antiestrogen • hormone responsiveness




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