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"Requirement of IGF Signaling for Alveolar Development and Differentiation in the Murine Mammary Gland"

by
Zhaoyu Sun
Interdisciplinary Biomedical Sciences Program

B.S. 1995, Laiyang Agricultural University, P.R. China
M.Sc. 2004, Kansas State University




Thesis Advisor: Terri Wood, Ph.D.
Professor
Department of Neurology & Neurosciences
University Hospital Cancer Center

Friday, May 7, 2010
Cancer Center, G1196, 9:00 A.M.


Abstract

The Insulin like growth factors (IGFs) and the IGF type 1 receptor (IGF-1R) are critical for normal mammary gland development in mice. In particular, IGF-I and the IGF-1R have demonstrated functions in formation and proliferation of terminal end buds (TEBs) 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-IR) under the control of the whey acidic protein (WAP) promoter.
Here, we provide evidence that the IGF-1R pathway is necessary for epithelial branch outgrowth and alveolar proliferation and differentiation during pregnancy. Specifically, we demonstrate that dnhIGF-IR expression decreases alveolar density by compromising epithelial cell proliferation but has no effect on epithelial cell death. Furthermore, we demonstrate that the presence of the dnhIGF-IR decreases milk protein -casein expression at P14.5 and causes deficits in lipid droplet formation. We also demonstrate that dnhIGF-IR expression compromises myoepithelial cell formation. The alterations in alveolar growth and differentiation resulting from transgene expression are transient, and the mammary glands appear normal by lactation day 5. Consistent with these results, average pup weights are normal in litters of lactating dams carrying the dnhIGF-1R transgene.
We further determined that IGF-IR regulates alveolar proliferation and differentiation through the IGF-IR/PI3K/Akt signaling pathway. We demonstrated that phosphorylation of Akt (Ser473) is decreased in acute IGF-I -stimulated dnhIGF-IR primary mammary epithelial cells (MECs). Furthermore, we demonstrated that dnhIGF-IR expression decreases IRS1, IRS2, and Stat5 expression at both the mRNA level and protein level in MECs. However, neither -casein or Stat5b are decreased at the mRNA level. These data show that IGF-1R signaling is necessary during pregnancy-alveolar development for normal induction of molecules with essential functions in alveolar differentiation. The data also suggest that cross talk of IGF-1R signaling pathway with other signaling pathways, such as the progesterone signaling pathway and/or the prolactin receptor signaling pathway, may regulate alveolar development and differentiation.


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