By systematically delineating the intricate hormonal processes involved in normal mammary gland development and relating them to breast cancer, our mission is to identify potential medical therapies for breast cancer based on these findings. We have proven that GH, through IGF-I, plays a pivotal role in mammary development during puberty and likely during pregnancy. By direct interaction with mammary fat pads, GH induces IGF-I mRNA. Through a potent permissive and synergistic interaction with E2, IGF-I stimulates TEB formation and mammary ductal morphogenesis, and later permits Pg and E2 to interact with it to form alveoli. We now have strong preliminary evidence that IGF-I may act by stimulating the formation of what we have called a """"""""mammary development unit (MDU)"""""""", consisting of a TEB in and around which MMP-9 is produced, along with new vessel formation, and an accumulation of mast cells that produce VEGF. MMP-9 may act to enhance the effect of IGF-I on ductal morphogenesis, and angiogenesis. Since IGF-I is known to induce growth of breast cancers, and inhibition of IGF-I can inhibit cancer development and normal development, we speculate that IGF- I represents a common thread linking normal and breast cancer development through similar mechanisms. Our future research will focus on evaluating the role of GH-induced IGF-I and its mechanism of action in mammary development, and cancer development. We propose to study the effects of GH and IGF-I in normal mammary development by examining the effects of IGF-I on formation of parameters of the MDU, and relate the findings to experimental human breast cancer development and treatment. These parameters will be examined in Ames dwarf animals (oophorectomized to remove endogenous Pg and E2), hypophysectomized, oophorectomized sexually immature mice, and nude mice. Animals will be treated with various combinations of hormones or inhibitors of IGF-I, MMP-9 or VEGF action, with and without E2 antagonists. Markers of IGF-I action (angiogenesis, MMP and VEGF production and involvement of IGFBP-3) will be evaluated by immunohistochemistry, in situ hybridization, electron microscopy and molecular biological and anatomical techniques. The potential role of IGF-I as a permissive factor for the action of PRL will also be determined.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064709-09
Application #
6830700
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Sussman, Daniel J
Project Start
1996-08-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
9
Fiscal Year
2005
Total Cost
$324,480
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Kleinberg, David L; Ruan, Weifeng; Yee, Douglas et al. (2007) Insulin-like growth factor (IGF)-I controls prostate fibromuscular development: IGF-I inhibition prevents both fibromuscular and glandular development in eugonadal mice. Endocrinology 148:1080-8
Carmichael, John D; Danoff, Ann; Milani, Daniela et al. (2006) GH peak response to GHRH-arginine: relationship to insulin resistance and other cardiovascular risk factors in a population of adults aged 50-90. Clin Endocrinol (Oxf) 65:169-77
Ruan, Weifeng; Fahlbusch, Fabian; Clemmons, David R et al. (2006) SOM230 inhibits insulin-like growth factor-I action in mammary gland development by pituitary independent mechanism: mediated through somatostatin subtype receptor 3? Mol Endocrinol 20:426-36
Ruan, Weifeng; Monaco, Marie E; Kleinberg, David L (2005) Progesterone stimulates mammary gland ductal morphogenesis by synergizing with and enhancing insulin-like growth factor-I action. Endocrinology 146:1170-8
Kleinberg, D L; Feldman, M; Ruan, W (2000) IGF-I: an essential factor in terminal end bud formation and ductal morphogenesis. J Mammary Gland Biol Neoplasia 5:17-Jul
Ruan, W; Powell-Braxton, L; Kopchick, J J et al. (1999) Evidence that insulin-like growth factor I and growth hormone are required for prostate gland development. Endocrinology 140:1984-9
Ruan, W; Kleinberg, D L (1999) Insulin-like growth factor I is essential for terminal end bud formation and ductal morphogenesis during mammary development. Endocrinology 140:5075-81