The research plan outlined in this proposal will elucidate the mechanisms by which the insulin-like growth factors, IGF-I and IGF-II, and their primary signaling receptor, the IGF type I receptor (IGF-IR) mediate growth and differentiation of cells in the mammary gland. The goal of the proposal is to test the hypotheses that: 1) the IGFs and IGF-IR are essential for mammary epithelial proliferation and for epithelial-stromal signaling, and 2) IGF-I and IGF-II have differential functions in mediating mammary gland growth and differentiation. Experiments in specific aim one utilize a mammary gland culture system to determine whether IGF signaling regulates cell cycle progression in the mammary gland by regulating expression and activation of both the G1 and G2 checkpoint complexes. These experiments also will elucidate the mechanisms for IGF/EGF interactions in mediating cell cycle progression during mammary development. In the second specific aim, a genetic approach will be used to test the role of IGF-IR signaling in EGF or TGF- mediated growth of mammary glands in vitro and in vivo. Experiments in aim two also will address the role of the IGF-IR in epithelial-stromal signaling in mammary development.
In aim three of the research plan, we will utilize additional genetic approaches to test whether IGF-I and IGF-II function differentially in mammary development. These experiments will include studies to determine whether IGF-II expression is directly regulated by progesterone in the mammary gland. The experimental data generated will have a significant impact on our understanding of IGF and IGF receptor function in normal development of this tissue. The IGFs and IGF-IR are among the increasing numbers of genes with proposed roles in both normal breast development and breast cancer, thus, results of these experiments also will provide a basis for understanding mechanisms of IGF action in breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060612-03
Application #
6699957
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Silva, Corinne M
Project Start
2002-03-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
3
Fiscal Year
2004
Total Cost
$268,708
Indirect Cost
Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Flannery, Clare A; Saleh, Farrah L; Choe, Gina H et al. (2016) Differential Expression of IR-A, IR-B and IGF-1R in Endometrial Physiology and Distinct Signature in Adenocarcinoma. J Clin Endocrinol Metab 101:2883-91
Flannery, Clare A; Rowzee, Anne M; Choe, Gina H et al. (2016) Development of a Quantitative PCR Assay for Detection of Human Insulin-Like Growth Factor Receptor and Insulin Receptor Isoforms. Endocrinology 157:1702-8
Rota, Lauren M; Albanito, Lidia; Shin, Marcus E et al. (2014) IGF1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors. Cancer Res 74:5668-79
Rota, Lauren M; Lazzarino, Deborah A; Ziegler, Amber N et al. (2012) Determining mammosphere-forming potential: application of the limiting dilution analysis. J Mammary Gland Biol Neoplasia 17:119-23
Sun, Zhaoyu; Shushanov, Sain; LeRoith, Derek et al. (2011) 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. Endocrinology 152:3233-45
Cannata, Dara; Lann, Danielle; Wu, Yingjie et al. (2010) Elevated circulating IGF-I promotes mammary gland development and proliferation. Endocrinology 151:5751-61
Rowzee, Anne M; Ludwig, Dale L; Wood, Teresa L (2009) Insulin-like growth factor type 1 receptor and insulin receptor isoform expression and signaling in mammary epithelial cells. Endocrinology 150:3611-9
Rowzee, Anne M; Lazzarino, Deborah A; Rota, Lauren et al. (2008) IGF ligand and receptor regulation of mammary development. J Mammary Gland Biol Neoplasia 13:361-70
Ning, Yun; Hoang, Bao; Schuller, Alwin G P et al. (2007) Delayed mammary gland involution in mice with mutation of the insulin-like growth factor binding protein 5 gene. Endocrinology 148:2138-47
Loladze, Aimee V; Stull, Malinda A; Rowzee, Anne M et al. (2006) Epithelial-specific and stage-specific functions of insulin-like growth factor-I during postnatal mammary development. Endocrinology 147:5412-23

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