title: Conditional overexpression of liver receptor homolog-1 in female mouse mammary epithelium results in altered mammary morphogenesis via the induction of TGF-β.
abstract: Liver receptor homolog-1 (LRH-1) is an orphan nuclear receptor that belongs to the NR5A subgroup of nuclear receptors. LRH-1 induces key genes to regulate metabolic process, ovarian function, cancer cell proliferation, and steroidogenesis. In the breast, LRH-1 modulates and synergizes with endogenous estrogen signaling to promote breast cancer cell proliferation. We used small interfering RNA knockdown strategies to deplete LRH-1 in breast cancer cells and followed with microarray analysis to identify LRH-1-dependent mechanisms. We identified key genes involved in TGF-β signaling to be highly responsive to LRH-1 knockdown. This relationship was validated in 2 breast cancer cell lines overexpressing LRH-1 in vitro and in a novel transgenic mouse with targeted LRH-1 overexpression in mammary epithelial cells. Notably, TGF-β signaling was activated in LRH-1-overexpressing breast cancer cells and mouse mammary glands. Further analyses of mammary gross morphology revealed a significant reduction in mammary lateral budding after LRH-1 overexpression. These findings suggest that the altered mammary morphogenesis in LRH-1 transgenic animals is mediated via enhanced TGF-β expression. The regulation of TGF-β isoforms and SMAD2/3-mediated downstream signaling by LRH-1 also implicates a potential contribution of LRH-1 in breast cancer. Collectively, these data demonstrate that LRH-1 regulates TGF-β expression and downstream signaling in mouse mammary glands.
authors.affiliation: Cancer Drug Discovery Laboratory (K.A.L., M.J.Y., Z.Z., R.S.C., A.L.C., C.D.C.) and Metabolism and Cancer Laboratory (K.A.B.), Prince Henry's Institute of Medical Research, Clayton, Victoria 3168, Australia; Environmental and Biotechnology Centre (K.A.L.), Swinburne University, Hawthorn, Victoria 3122, Australia; and Department of Biochemistry and Molecular Biology (C.D.C.), Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Kyren A
authors.initials: KA
authors.lastname: Lazarus
authors.forename: Kristy A
authors.initials: KA
authors.lastname: Brown
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhao
authors.forename: Rhiannon S
authors.initials: RS
authors.lastname: Coulson
authors.forename: Ashwini L
authors.initials: AL
authors.lastname: Chand
authors.forename: Colin D
authors.initials: CD
authors.lastname: Clyne
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D061986:MCF-7 Cells; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009024:Morphogenesis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C082631:NR5A2 protein, human; D009363:Neoplasm Proteins; C431936:Nr5a2 protein, mouse; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D051896:Smad Proteins, Receptor-Regulated; D016212:Transforming Growth Factor beta