The overall goal of the proposed research is to investigate molecular mechanisms underlying growth control in the mammary gland in vivo, focusing on the role of CCAAT/enhancer binding protein delta (C/EBP-delta). Mammary tissue is unique in its capacity to undergo rapid and repeated cycles of proliferation, differentiation, and involution. However, the basic molecular mechanisms involved in the response of mammary epithelial cells to proliferative and anti-proliferative signals are unclear. C/EBP-delta is a member of a family of DNA binding proteins important in the regulation of genes involved in growth and differentiation in a variety of tissues. The applicant's lab was the first to report the unique pattern of C/EBP isoforms expressed in the mammary gland, implicating the delta isoform as a primary participant in mammary growth regulation. Both in vivo and in vitro studies indicate an association between C/EBP-delta and growth arrest in mammary epithelial cells. The experiments outlined in this proposal will use lactating mice as an animal model to provide new information regarding the regulation of C/EBP-delta in the mammary gland in vivo. In particular, the relationship between C/EBP-delta gene expression and post-lactational mammary gland involution and apoptosis (programmed cell death) will be investigated. C/EBP and apoptosis-associated gene expression will be investigated through lactation and involution in Specific Aim 1, and C/EBP-delta transcriptional regulation will be evaluated in Aim 2. In situ expression of C/EBP isoforms and apoptosis-associated mRNAs will be examined in Aim 3.
Aim 4 will address C/EBP-delta function using null mutation transgenic knock-out mice. A better understanding of the molecular mechanisms of growth regulation is crucial to understanding the distinction between controlled growth and uncontrolled growth, as in breast cancer. Breast cancer is the number one form of cancer and the second leading cause of cancer deaths among women in the United States. It is important to investigate the regulation of genes, such as C/EBP-delta, involved in growth control in mammary epithelial cells. Advances in understanding the molecular mechanisms underlying growth control promise to contribute to both treatment and prevention of breast cancer.
| Gigliotti, Andrew P; Johnson, Peter F; Sterneck, Esta et al. (2003) Nulliparous CCAAT/enhancer binding proteindelta (C/EBPdelta) knockout mice exhibit mammary gland ductal hyperlasia. Exp Biol Med (Maywood) 228:278-85 |
| Gigliotti, A P; DeWille, J W (1999) Local signals induce CCAAT/enhancer binding protein-delta (C/EBP-delta) and C/EBP-beta mRNA expression in the involuting mouse mammary gland. Breast Cancer Res Treat 58:57-63 |
| Gigliotti, A P; DeWille, J W (1998) Lactation status influences expression of CCAAT/enhancer binding protein isoform mRNA in the mouse mammary gland. J Cell Physiol 174:232-9 |
