Progressive loss of estrogen receptor alpha cofactor recruitment in endocrine resistance.
Differential expression of estrogen receptor-alpha (ERalpha) 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 ERalpha cofactor recruitment to the estrogen-dependent pS2 gene and reduced requirement for cofactor expression. Maximal estrogen induced pS2 induction requires ERalpha 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.
Naughton
Catherine
C
Edinburgh Cancer Research Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, United Kingdom. Catherine.Naughton@ed.ac.uk
MacLeod
Kenneth
K
Kuske
Barbara
B
Clarke
Robert
R
Cameron
David A
DA
Langdon
Simon P
SP
D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004703:Endocrine System / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D012333:RNA, Messenger