title: The transcriptional co-factor RIP140 regulates mammary gland development by promoting the generation of key mitogenic signals.
abstract: Nuclear receptor interacting protein (Nrip1), also known as RIP140, is a co-regulator for nuclear receptors that plays an essential role in ovulation by regulating the expression of the epidermal growth factor-like family of growth factors. Although several studies indicate a role for RIP140 in breast cancer, its role in the development of the mammary gland is unclear. By using RIP140-null and RIP140 transgenic mice, we demonstrate that RIP140 is an essential factor for normal mammary gland development and that it functions by mediating oestrogen signalling. RIP140-null mice exhibit minimal ductal elongation with no side-branching, whereas RIP140-overexpressing mice show increased cell proliferation and ductal branching with age. Tissue recombination experiments demonstrate that RIP140 expression is required in both the mammary epithelial and stromal compartments for ductal elongation during puberty and that loss of RIP140 leads to a catastrophic loss of the mammary epithelium, whereas RIP140 overexpression augments the mammary basal cell population and shifts the progenitor/differentiated cell balance within the luminal cell compartment towards the progenitors. For the first time, we present a genome-wide global view of oestrogen receptor-α (ERα) binding events in the developing mammary gland, which unravels 881 ERα binding sites. Unbiased evaluation of several ERα binding sites for RIP140 co-occupancy reveals selectivity and demonstrates that RIP140 acts as a co-regulator with ERα to regulate directly the expression of amphiregulin (Areg), the progesterone receptor (Pgr) and signal transducer and activator of transcription 5a (Stat5a), factors that influence key mitogenic pathways that regulate normal mammary gland development.
authors: Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK.
authors: Jaya
authors: J
authors: Nautiyal
authors: Jennifer H
authors: JH
authors: Steel
authors: Meritxell Rosell
authors: MR
authors: Mane
authors: Olayiwola
authors: O
authors: Oduwole
authors: Ariel
authors: A
authors: Poliandri
authors: Xanthippi
authors: X
authors: Alexi
authors: Nicholas
authors: N
authors: Wood
authors: Matti
authors: M
authors: Poutanen
authors: Wilbert
authors: W
authors: Zwart
authors: John
authors: J
authors: Stingl
authors: Malcolm G
authors: MG
authors: Parker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006133:Growth Substances / Q000235:genetics* / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000078723:Nuclear Receptor Interacting Protein 1; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006133:Growth Substances; C000627128:Nrip1 protein, mouse; D009687:Nuclear Proteins; D000078723:Nuclear Receptor Interacting Protein 1; D014157:Transcription Factors; D004958:Estradiol
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