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Progressive Loss of Estrogen Receptor Cofactor Recruitment in Endocrine Resistance

Edinburgh Cancer Research Centre (C.N., K.M., B.K., D.A.C., S.P.L.), University of Edinburgh, Edinburgh EH4 2XR, United Kingdom; and Lombardi Comprehensive Cancer Center (R.C.), Georgetown University School of Medicine, Washington, D.C., 20057

Address all correspondence and requests for reprints to: Catherine Naughton, Edinburgh Cancer Research Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom. E-mail: Catherine.Naughton{at}ed.ac.uk.

Differential expression of estrogen receptor- (ER) 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 chromatin immunoprecipitation and RNA interference, that there is a progressive loss of ER cofactor recruitment to the estrogen-dependent pS2 gene and reduced requirement for cofactor expression. Maximal estrogen induced pS2 induction requires ER 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   ERα

Coregulators:   SRC-1  |  GRIP1  |  AIB1  |  NCOR  |  SMRT

Ligands:   17β-Estradiol

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