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This version published online on July 31, 2007
Molecular Endocrinology, doi:10.1210/me.2007-0110
A more recent version of this article appeared on November 1, 2007
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Submitted on February 27, 2007
Accepted on July 25, 2007

Progressive loss of Estrogen Receptor {alpha} (ER{alpha}) cofactor recruitment in endocrine resistance

Catherine Naughton*, Kenneth MacLeod, Barbara Kuske, Robert Clarke, David A. Cameron, and Simon P. Langdon

Edinburgh Cancer Research Centre, University of Edinburgh, Crewe Rd South, Edinburgh, EH4 2XR, UK; Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Room W405A Research Building, 3970 Reservoir Road Northwest, Washington, DC 20057, USA

* To whom correspondence should be addressed. E-mail: Catherine.Naughton{at}ed.ac.uk.

Differential expression of estrogen receptor-{alpha} (ER{alpha}) cofactors has been implicated in endocrine resistance in breast cancer. Using a three stage MCF-7 cell-based model that emulates the clinical manifestation of acquired endocrine resistant breast cancer we now show, using a combination of ChIP and RNAi, that there is a progressive loss of ER{alpha} cofactor recruitment to the estrogen-dependent pS2 gene and reduced requirement for cofactor expression. Maximal estrogen induced pS2 induction requires ER{alpha} and cofactor recruitment in MCF-7 cells but in the progression to endocrine resistance these requirements are altered and expression has become less dependent on cofactors. Additionally, in estrogen resistant MCF-7 cells there is a global loss of requirement of individual cofactors for proliferative cell growth indicating that other genes have lost the need for transcriptional cofactors. This loss of the requirement for cofactors may represent an important mechanism for gene misregulation in cancer.
Key words: Estrogen receptor • AIB1 • SRC-1 • SRC-2 • endocrine resistance

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα
Coregulators:   SRC-1  |  GRIP1  |  AIB1  |  NCOR  |  SMRT
Ligands:   17β-Estradiol



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