title: ICI 182,780 induces P-cadherin overexpression in breast cancer cells through chromatin remodelling at the promoter level: a role for C/EBPbeta in CDH3 gene activation.
abstract: CDH3/P-cadherin is a classical cadherin. Overexpression of which has been associated with proliferative lesions of high histological grade, decreased cell polarity and poor survival of patients with breast cancer. In vitro studies showed that it can be up-regulated by ICI 182,780, suggesting that the lack of ERalpha signalling is responsible for the aberrant P-cadherin overexpression and for its role in inducing breast cancer cell invasion and migration. However, the mechanism by which ER-signalling inhibition leads to P-cadherin expression is still unknown. The aim of this study was to explore the molecular mechanism linking the ERalpha-signalling and P-cadherin-regulated expression in breast cancer cell lines. This study showed that ICI 182,780 is able to increase CDH3 promoter activity, inducing high levels of the active chromatin mark H3 lysine 4 dimethylation. We also observed, for the first time, that the transcription factor C/EBPbeta is able to up-regulate CDH3 promoter activity in breast cancer cells. Moreover, we showed that the expression of P-cadherin and C/EBPbeta are highly associated in human breast carcinomas and linked with a worse prognosis of breast cancer patients. This study demonstrates the existence of an epigenetic regulation by which ICI 182,780 up-regulates P-cadherin expression in MCF-7/AZ breast cancer cells through chromatin remodelling at CDH3 promoter, bringing forward the growing evidence that ERalpha signalling-abrogation by anti-oestrogens is able to induce the expression of ERalpha-repressed genes which, in the appropriate cell biology context, may contribute to a breast cancer cell invasion phenotype.CDH3 GenBank accession no. NT_010498.
authors.affiliation: Institute of Life and Health Sciences, School of Health Sciences of Minho University, Braga, Portugal.
authors.forename: André
authors.initials: A
authors.lastname: Albergaria
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Ribeiro
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinho
authors.forename: Fernanda
authors.initials: F
authors.lastname: Milanezi
authors.forename: Vítor
authors.initials: V
authors.lastname: Carneiro
authors.forename: Bárbara
authors.initials: B
authors.lastname: Sousa
authors.forename: Sónia
authors.initials: S
authors.lastname: Sousa
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Machado
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Joana
authors.initials: J
authors.lastname: Paredes
authors.forename: Fernando
authors.initials: F
authors.lastname: Schmitt
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D022782:CCAAT-Enhancer-Binding Protein-beta; C512197:CDH3 protein, human; D015820:Cadherins; D047628:Estrogen Receptor alpha; D014157:Transcription Factors; D000077267:Fulvestrant; D004958:Estradiol