Based on the preliminary investigations which are summarized in the body of their application, they have demonstrated that significant levels of CSF-1Rs (the fms-protooncogene product) are expressed by neoplastic mammary epithelial cells in vivo and in vitro; and that activation of this receptor on breast carcinoma cells by its cognate ligand, the macrophage-colony stimulating factor, CSF-1 increases the expression & cell surface localization of specific proteases and stimulates the invasion of basement membrane analogues such as human amnionic membrane and Matrigel. They have also demonstrated in vitro that levels of expression of this receptor are greatly augmented by glucocorticoids in some breast carcinoma-derived cultured cell lines, but not in others. Based on these observations, they have hypothesized that transcription and level of expression of CSF-1R is increased in (benign and neoplastic) mammary epithelial cells by glucocorticoids and down regulated by antagonists such as RU-486 in vivo and in vitro. They have also hypothesized that the regulation of transcription of the first CSF-1R promoter by glucocorticoids in breast carcinoma cells is further modulated by one or more accessory transcription factors which explain why this promoter is responsive to glucocorticoids in some cell lines and whose action in vivo to render the CSF-1R promoter responsive (or refractory) to glucocorticoids--ubiquitous and omnipresent steroid hormones--may help explain the variance in levels of CSF-1R expression observed in vivo in breast carcinoma specimens. They propose to test these hypotheses by continuing the investigations of steroid hormone regulation of CSF-1R gene expression--specifically focusing on the more complete characterization of those elements of the first CSF-1R promoter (and the proteins which bind to them) responsible for the observed stimulation of CSF-1R gene transcription in BT20 and SKBR3 but not MCF-7 breast carcinoma cell lines and determining whether the levels of expression of these """"""""accessory"""""""" factors correlates with the level of expression of CSF-1R observed in human breast carcinoma tissue specimens. They also propose to determine whether glucocorticoids and their antagonists modulate the expression of CSF-1R in human breast carcinoma specimens maintained ex vivo in short-term organ culture and in vivo in nude mice.
