title: Mechanisms of estrogen receptor antagonism toward p53 and its implications in breast cancer therapeutic response and stem cell regulation.
abstract: Estrogen receptor alpha (ERalpha) plays an important role in the onset and progression of breast cancer, whereas p53 functions as a major tumor suppressor. We previously reported that ERalpha binds to p53, resulting in inhibition of transcriptional regulation by p53. Here, we report on the molecular mechanisms by which ERalpha suppresses p53's transactivation function. Sequential ChIP assays demonstrated that ERalpha represses p53-mediated transcriptional activation in human breast cancer cells by recruiting nuclear receptor corepressors (NCoR and SMRT) and histone deacetylase 1 (HDAC1). RNAi-mediated down-regulation of NCoR resulted in increased endogenous expression of the cyclin-dependent kinase (CDK)-inhibitor p21(Waf1/Cip1) (CDKN1A) gene, a prototypic transcriptional target of p53. While 17beta-estradiol (E2) enhanced ERalpha binding to p53 and inhibited p21 transcription, antiestrogens decreased ERalpha recruitment and induced transcription. The effects of estrogen and antiestrogens on p21 transcription were diametrically opposite to their known effects on the conventional ERE-containing ERalpha target gene, pS2/TFF1. These results suggest that ERalpha uses dual strategies to promote abnormal cellular proliferation: enhancing the transcription of ERE-containing proproliferative genes and repressing the transcription of p53-responsive antiproliferative genes. Importantly, ERalpha binds to p53 and inhibits transcriptional activation by p53 in stem/progenitor cell-containing murine mammospheres, suggesting a potential role for the ER-p53 interaction in mammary tissue homeostasis and cancer formation. Furthermore, retrospective studies analyzing response to tamoxifen therapy in a subset of patients with ER-positive breast cancer expressing either wild-type or mutant p53 suggest that the presence of wild-type p53 is an important determinant of positive therapeutic response.
authors.affiliation: Department of Pharmacology and Therapeutics, Center for Genetics and Pharmacology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Santhi D
authors.initials: SD
authors.lastname: Konduri
authors.forename: Rajesh
authors.initials: R
authors.lastname: Medisetty
authors.forename: Wensheng
authors.initials: W
authors.lastname: Liu
authors.forename: Benny Abraham
authors.initials: BA
authors.lastname: Kaipparettu
authors.forename: Pratima
authors.initials: P
authors.lastname: Srivastava
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.forename: Peter
authors.initials: P
authors.lastname: Fritz
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Swetzig
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Gardner
authors.forename: Sohaib A
authors.initials: SA
authors.lastname: Khan
authors.forename: Gokul M
authors.initials: GM
authors.lastname: Das
mesh_terms: D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D004958:Estradiol / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D016158:Genes, p53; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism; D011401:Promoter Regions, Genetic; D013629:Tamoxifen / Q000494:pharmacology; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017931:DNA Primers; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D050505:Mutant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D004958:Estradiol; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1