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Epithelial-Specific and Stage-Specific Functions of Insulin-Like Growth Factor-I during Postnatal Mammary Development

Department of Neural and Behavioral Sciences (A.V.L., A.M.R., J.D., J.H.L.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; Department of Molecular and Cellular Physiology (M.A.S.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; Maine Center for Osteoporosis Research and Education (C.J.R.), St. Joseph Hospital, Bangor, Maine 04401; Department of Medicine (D.L.), Mt. Sinai School of Medicine, New York, New York 10029; University of Nebraska Medical Center (K.-U.W.), Omaha, Nebraska 68198; Laboratory of Genetics and Physiology (L.H.), National Institutes of Health, Bethesda, Maryland 20892; and Department of Neurology and Neurosciences (T.L.W.), New Jersey Medical School, University of Medicine and Dentistry New Jersey, Newark, New Jersey 07103

Address all correspondence and requests for reprints to: Teresa L. Wood, Department of Neurology and Neurosciences H506, New Jersey Medical School, University of Medicine and Dentistry New Jersey, 185 South Orange Avenue, Newark, New Jersey 07103. E-mail: woodte{at}umdnj.edu.

Postnatal development of the mammary gland requires interactions between the epithelial and stromal compartments, which regulate actions of hormones and growth factors. IGF-I is expressed in both epithelial and stromal compartments during postnatal development of the mammary gland. However, little is known about how local expression of IGF-I in epithelium or stroma regulates mammary growth and differentiation during puberty and pregnancy-induced alveolar development. The goal of this study was to investigate the mechanisms of IGF-I actions in the postnatal mammary gland and test the hypothesis that IGF-I expressed in stromal and epithelial compartments has distinct functions. We established mouse lines with inactivation of the igf1 gene in mammary epithelium by crossing igf1/loxP mice with mouse lines expressing Cre recombinase under the control of either the mouse mammary tumor virus long-terminal repeat or the whey acidic protein gene promoter. Epithelial-specific loss of IGF-I during pubertal growth resulted in deficits in ductal branching. In contrast, heterozygous reduction of IGF-I throughout the gland decreased expression of cyclins A2 and B1 during pubertal growth and resulted in alterations in proliferation of the alveolar epithelium and milk protein levels during pregnancy-induced differentiation. Reduction in epithelial IGF-I at either of these stages had no effect on these indices. Taken together, our results support distinct roles for IGF-I expressed in epithelial and stromal compartments in mediating growth of the postnatal mammary gland.

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