) For women between the ages of 15 and 54 breast cancer is the most common cause of death due to cancer. The mortality rates for breast cancer have remained stable for the last 50 years. The development of effective treatments for breast cancer would be facilitated by an improved understanding of the cellular mechanisms that underlie the proliferation and differentiation of normal mammary epithelial cells. In many estrogen receptor (ER)-positive cancers the nuclear oncogene cyclin D1 is overexpressed. Cyclin D1 is essential for murine breast epithelial cell development during pregnancy. Both in vitro in breast epithelial cells and in vivo in the mammary gland cyclin D1 is induced during differentiation. In vitro studies suggest that, in the absence of estradiol, the transcriptional functions of the ER are induced during differentiation and this induction correlates with the increase in cyclin D1 levels. This suggests a causal relationship between these two events. Consistent with this, cyclin D1 can bind to the ER and activate its transcriptional functions. This proposal is aimed at better understanding the role of cyclin D1 in the breast, both in its relationship to the ER and cyclin-dependent kinase 4. The interaction between cyclin D1 and the ER will be characterized at the molecular level through a detailed genetic and biochemical analysis. Methods will be developed to detect cyclin D1-ER complexes in either differentiating breast epithelial cells or in cell lines which overexpress cyclin D1, which has hitherto been observed only in vitro. An effort will be made to understand the biological significance of the cyclin D1-ER interaction. To this end, an investigation of the biological importance of cyclin D1 function during in vitro differentiation and a genetic dissection of the cyclin D1-ER interaction will be undertaken. The results of these studies will enable the physiological significance of cyclin D1-mediated activation of the ER to be tested in genetically manipulated mice. The objective of the proposed work is to understand how cyclin D1 activates the transcriptional functions of the ER and to establish a physiologic role of this interaction in breast epithelial proliferation, development and/or neoplasia.
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