title: IGF-2 is a mediator of prolactin-induced morphogenesis in the breast.
abstract: The mechanisms by which prolactin controls proliferation of mammary epithelial cells (MECs) and morphogenesis of the breast epithelium are poorly understood. We show that cyclin D1(-/-) MECs fail to proliferate in response to prolactin and identify IGF-2 as a downstream target of prolactin signaling that lies upstream of cyclin D1 transcription. Ectopic IGF-2 expression restores alveologenesis in prolactin receptor(-/-) epithelium. Alveologenesis is retarded in IGF-2-deficient MECs. IGF-2 and prolactin receptor mRNAs colocalize in the mammary epithelium. Prolactin induces IGF-2 mRNA and IGF-2 induces cyclin D1 protein in primary MECs. Thus, IGF-2 is a mediator of prolactin-induced alveologenesis; prolactin, IGF-2, and cyclin D1, all of which are overexpressed in breast cancers, are components of a developmental pathway in the mammary gland.
authors.affiliation: Department of Surgical Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA. cathrin.brisken@isrec.unil.ch
authors.forename: Cathrin
authors.initials: C
authors.lastname: Brisken
authors.forename: Ayyakkannu
authors.initials: A
authors.lastname: Ayyannan
authors.forename: Cuc
authors.initials: C
authors.lastname: Nguyen
authors.forename: Anna
authors.initials: A
authors.lastname: Heineman
authors.forename: Ferenc
authors.initials: F
authors.lastname: Reinhardt
authors.forename: Jian
authors.initials: J
authors.lastname: Tan
authors.forename: S K
authors.initials: SK
authors.lastname: Dey
authors.forename: G Paolo
authors.initials: GP
authors.lastname: Dotto
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
authors.forename: Tian
authors.initials: T
authors.lastname: Jan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D002277:Carcinoma / Q000235:genetics; D002352:Carrier Proteins; D002455:Cell Division / Q000235:genetics*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000172:deficiency* / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005796:Genes / Q000187:drug effects / Q000235:genetics; D005820:Genetic Testing; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology; D011388:Prolactin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053245:RANK Ligand; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D011980:Receptors, Progesterone / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D011980:Receptors, Progesterone; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D019938:Cyclin D1; D011374:Progesterone; D007335:Insulin-Like Growth Factor II; D011388:Prolactin