title: Bromodomain 4 activation predicts breast cancer survival.
abstract: Previous work identified the Rap1 GTPase-activating protein Sipa1 as a germ-line-encoded metastasis modifier. The bromodomain protein Brd4 physically interacts with and modulates the enzymatic activity of Sipa1. In vitro analysis of a highly metastatic mouse mammary tumor cell line ectopically expressing Brd4 demonstrates significant reduction of invasiveness without altering intrinsic growth rate. However, a dramatic reduction of tumor growth and pulmonary metastasis was observed after s.c. implantation into mice, implying that activation of Brd4 may somehow be manipulating response to tumor microenvironment in the in vivo setting. Further in vitro analysis shows that Brd4 modulates extracellular matrix gene expression, a class of genes frequently present in metastasis-predictive gene signatures. Microarray analysis of the mammary tumor cell lines identified a Brd4 activation signature that robustly predicted progression and/or survival in multiple human breast cancer datasets analyzed on different microarray platforms. Intriguingly, the Brd4 signature also almost perfectly matches a molecular classifier of low-grade tumors. Taken together, these data suggest that dysregulation of Brd4-associated pathways may play an important role in breast cancer progression and underlies multiple common prognostic signatures.
authors.affiliation: Laboratory of Cancer Biology and Genetics and Laboratory of Population Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Nigel P S
authors.initials: NP
authors.lastname: Crawford
authors.forename: Jude
authors.initials: J
authors.lastname: Alsarraj
authors.forename: Luanne
authors.initials: L
authors.lastname: Lukes
authors.forename: Renard C
authors.initials: RC
authors.lastname: Walker
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Officewala
authors.forename: Howard H
authors.initials: HH
authors.lastname: Yang
authors.forename: Maxwell P
authors.initials: MP
authors.lastname: Lee
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Kent W
authors.initials: KW
authors.lastname: Hunter
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D030541:Databases, Genetic; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011960:Receptors, Estrogen / Q000378:metabolism; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D009687:Nuclear Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins