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.
