title: Decreased IGF type 1 receptor signaling in mammary epithelium during pregnancy leads to reduced proliferation, alveolar differentiation, and expression of insulin receptor substrate (IRS)-1 and IRS-2.
abstract: The IGFs and the IGF type 1 receptor (IGF-1R) are essential mediators of normal mammary gland development in mice. IGF-I and the IGF-1R have demonstrated functions in formation and proliferation of terminal end buds and in ductal outgrowth and branching during puberty. To study the functions of IGF-1R during pregnancy and lactation, we established transgenic mouse lines expressing a human dominant-negative kinase dead IGF-1R (dnhIGF-1R) under the control of the whey acidic protein promoter. We provide evidence that the IGF-1R pathway is necessary for normal epithelial proliferation and alveolar formation during pregnancy. Furthermore, we demonstrate that the whey acidic protein-dnhIGF-1R transgene causes a delay in alveolar differentiation including lipid droplet formation, lumen expansion, and β-casein protein expression. Analysis of IGF-1R signaling pathways showed a decrease in P-IGF-1R and P-Akt resulting from expression of the dnhIGF-1R. We further demonstrate that disruption of the IGF-1R decreases mammary epithelial cell expression of the signaling intermediates insulin receptor substrate (IRS)-1 and IRS-2. No alterations were observed in downstream signaling targets of prolactin and progesterone, suggesting that activation of the IGF-1R may directly regulate expression of IRS-1/2 during alveolar development and differentiation. These data show that IGF-1R signaling is necessary for normal alveolar proliferation and differentiation, in part, through induction of signaling intermediates that mediate alveolar development.
authors.affiliation: Department Neurology & Neuroscience, Cancer Center H1200, New Jersey Medical School/University of Medicine and Dentistry of New Jersey, 205 South Orange Avenue, Newark, New Jersey 07101-1709, USA.
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Sun
authors.forename: Sain
authors.initials: S
authors.lastname: Shushanov
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Wood
mesh_terms: D000818:Animals; D002364:Caseins / Q000235:genetics; D002454:Cell Differentiation; D016764:Cell Polarity; D049109:Cell Proliferation; D005260:Female; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D002364:Caseins; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt