The IGF ligands, IGF-I and IGF-II, and the IGF type I receptor (IGF-IR) have demonstrated roles in growth of mammary epithelium during normal development. Moreover, the IGFs and IGF-IR promote proliferation of breast cancer cells and are implicated in incidence and growth of breast cancers. Our previous studies demonstrated that IGF-I and IGF-II are distinctly expressed during pubertal and pregnancy-induced development of the mammary epithelium. During the previous funding period, we demonstrated that IGF-I regulates cell cycle progression in mammary epithelial cells and showed unique roles for IGF-I expressed in epithelial and stromal compartments of the developing mammary gland. We further elucidated how patterning of IGF-II expression is regulated in the mammary epithelium. Recent data suggest that the IGF ligands can signal through heterodimers of the IGF-IR and the insulin receptor (IR) in addition to homodimers of the IGF-IR. Moreover, a splice variant of the IR known as the IR-A isoform, has high specificity for IGF-II but not IGF-I. Our preliminary data show that mammary specific deletion of the IR during alveolar differentiation results in significant disruption of alveolar development and lactation. Furthermore, analysis of receptor expression suggests that the ratio of the two IR isoforms varies in mammary epithelial cells during pregnancy and lactation and that a significant portion of the IGF-IR exists as a hybrid receptor with the IR in mammary epithelial cells. Thus, the goal of the experiments proposed in this application is to test the hypothesis that the different IGF signaling receptors have distinct functions in alveolar differentiation and lactation. To test this hypothesis, we propose both in vitro experiments and in vivo transgenic studies to activate or disrupt signaling through the IRs, IGF-IR and hybrid receptors in mammary epithelial cells. Public Health Relevance Statement: The results of the proposed experiments will elucidate IGF receptor-specific actions and downstream signaling pathways in proliferation, survival and differentiation of normal mammary epithelial cells. These studies will also have important implications for the roles of these receptors and pathways in breast cancers.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Silva, Corinne M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Medicine & Dentistry of NJ
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 11 publications