Impact of C-neu/erbB2 on Estrogen and Estrogen Receptor Alpha-Dependent Proliferation of Mammary Ductal Epithelial Cells

Estrogen and progesterone, signaling through their cognate receptors- (ER and PR, respectively), promote the growth of mammary glands via growth factors which signal through the family of erbB receptors, such as C- neu/erbB2. We have made the paradoxical observation that in transgenic mice overexpressing C-neu, in which mammary tumors arise, mammary growth is, in fact, compromised during puberty without any gross impairment in growth during pregnancy. Our hypothesis is that (a) the individual and combined effects of ER, PR and/or C- neu depends on the mammary epithelial sub-type and the interactions among these receptors, (b)the net outcome of these interactions is to direct the developmental fate of the various epithelial subclasses and (c) a perturbation in these interactions, resulting from either an altered expression or signaling through these receptors leads to aberrant morphogenesis and neoplasia. Accordingly, we propose: (1) To examine the expression patterns of ER, PR and C-neu in mammary glands of wild type and C-neu transgenic mice during various developmental states and their relationships to cells undergoing proliferation; and, 2) To examine the growth patterns of mammary glands of C-neu transgenic mice upon serial transplantation into de-epithelialized fat pads. Our proposed studies will identify changes conducive to tumorigenesis, occurring in response to C-neu over- expression during early mammary development; this, in turn, can help to devise prophylatic strategies aimed at prevention and hence, its significance. The original document contains color images. All DTIC reproductions will be in black and white.