The endocrine mammogens estrogen and progesterone drive not only normal but also neoplastic mammary growth. Underlying mechanisms are poorly understood but no doubt involve the regulation of tissue intermediaries such as Insulin-like Growth Factors (IGFs) which are potent mitogens for normal mammary cells in vitro and have been implicated in the uncontrolled, neoplastic growth of these cells. Using slow-release plastic implants to treat small regions of the mouse mammary gland in situ, we recently demonstrated localized synergy of IGF with estrogen to stimulate ductal growth. At the doses used, neither estrogen or IGF-I alone stimulated the gland. This effect, along with the presence of abundant IGF-I message in the gland, is strong evidence that IGF-I is a normal, locally-acting ductal mammogen. We now propose to investigate local hormonal regulation of the IGF system and have developed a completely novel in vivo research system to do so. Slow-release implants containing antiestrogen or antiprogesterone are used to ablate cognate receptor action; localized disruption of steroid- dependent gene expression is detectable using standard methods such as Northern hybridization analysis. The capacity to relate steroid action to growth factor regulation is crucial to understanding glandular regulation in normal and pathological circumstances. Indeed, this single point is the focus of the RFA to which this proposal responds. The clearcut capability of our system to link steroid/growth factor modulation in a straightforward, unambiguous manner is described in preliminary studies. This system therefore promises direct answers to many questions concerning estrogen and progesterone regulation of the IGF system within the normal, preneoplastic and neoplastic gland. This new approach will be used to investigate estrogen and progesterone regulation of IGF-I, IGF-II, IGF type 1 and type 2 receptors, as well as certain IGF binding proteins in vivo. It is expected that the details of hormonal regulation of paracrine and negative feedback regulation of IGF action will come into focus. Growth-regulatory functions for specific binding proteins, inferred from the above experiments will be further defined by implanting mutant forms of IGI to perturb normal activity and unmask local actions. Our ability to relate gene expression to well- defined, biologically relevant end points within the gland (ductal growth versus inhibition), means that strong inferences concerning the functional importance of hormonal regulation of the IGF system will be forthcoming.
| Silberstein, Gary B; Dressler, Gregory R; Van Horn, Katharine (2002) Expression of the PAX2 oncogene in human breast cancer and its role in progesterone-dependent mammary growth. Oncogene 21:1009-16 |
| Silberstein, G B; Van Horn, K; Strickland, P et al. (1997) Altered expression of the WT1 wilms tumor suppressor gene in human breast cancer. Proc Natl Acad Sci U S A 94:8132-7 |
| Silberstein, G B; Van Horn, K; Shyamala, G et al. (1996) Progesterone receptors in the mouse mammary duct: distribution and developmental regulation. Cell Growth Differ 7:945-52 |
