title: The insulin receptor plays an important role in secretory differentiation in the mammary gland.
abstract: Insulin is known to be an important regulator of milk secretion in the lactating mammary gland. Here we examine the role of insulin signaling in mammary development in pregnancy using a mouse with a floxed insulin receptor (IR) crossed with a mouse expressing Cre specifically in the mammary gland. In the mammary glands of these IR(fl/fl) Cre(+) mice, expression of IR is significantly diminished throughout development. Glands from these mice had 50% fewer alveoli at midpregnancy; casein and lipid droplets were diminished by 60 and 75%, respectively, indicating a role for IR both in alveolar development and differentiation. In an acinar preparation from mammary epithelial cells (MEC) isolated from pregnant mice, insulin stimulated lumen formation, mammary cell size, acinar size, acinar casein content, and the formation of lipid droplets with a Km of ∼1.7 nM. IGF-I and IGF-II had no effect at concentrations below 50 nM, and a function blocking antibody to the IGF type 1 receptor did not alter the response to insulin. We conclude that insulin interacting with IR is essential for mammary differentiation during murine pregnancy. Using array analysis, we then examined the expression of genes up- or downregulated >1.5-fold in the IR(fl/fl) Cre(+) MECs, finding significant downregulation of differentiation specific genes and upregulation of cell cycle and extracellular matrix genes. We conclude that insulin fosters differentiation and may inhibit cell proliferation in the mammary gland of the midpregnant mouse.
authors: Department of Physiology and Biophysics, University of Colorado School of Medicine, Aurora, Colorado;
authors: Margaret C
authors: MC
authors: Neville
authors: Patricia
authors: P
authors: Webb
authors: Palaniappan
authors: P
authors: Ramanathan
authors: Meridee P
authors: MP
authors: Mannino
authors: Chiara
authors: C
authors: Pecorini
authors: Jenifer
authors: J
authors: Monks
authors: Steven M
authors: SM
authors: Anderson
authors: Paul
authors: P
authors: MacLean
mesh_terms: D061354:Acinar Cells / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002469:Cell Separation; D003599:Cytoskeleton / Q000378:metabolism; D004848:Epithelium / Q000254:growth & development; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D007328:Insulin / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D019426:Integrases / Q000096:biosynthesis / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000254:growth & development*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000166:cytology; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation
chemical_list: D007328:Insulin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D011972:Receptor, Insulin; C045073:Cre recombinase; D019426:Integrases
keywords: acinar culture; mammary development
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