Effect of c-neu/ ErbB2 expression levels on estrogen receptor alpha-dependent proliferation in mammary epithelial cells: implications for breast cancer biology.

Mammary development and tumorigenesis are profoundly influenced by signaling pathways under the control of c-erbB2/c-neu and estrogen receptor alpha (ERalpha). Signaling through ERalpha is essential for ductal growth during puberty. In mice overexpressing wild-type c-neu in mammary epithelial cells, Tg (c-neu), ductal growth is impaired. An impeded signaling through ERalpha is also observed in a subset of human mammary tumors that overexpress erbB2. However, ductal growth is also impaired in the absence of c-neu in mouse mammary epithelial cells. To resolve this apparent paradox, we examined the relationship between c-neu expression and estrogen/ERalpha-dependent cell proliferation in pubertal Tg (c-neu). We report that proliferation in both terminal end buds and ducts is associated with ERalpha-positive cells, including those that coexpress c-neu, and is abolished in the absence of circulating estradiol. Tg (c-neu) contains hyperplastic mammary ducts with high proliferative index and coexpression of both ERalpha and c-neu in the dividing cells. These findings suggest that c-neu promotes ERalpha-dependent proliferation, and that this is responsible for the presence of hyperplastic ducts. Some of the hyperplastic ducts have acinar structures, indicative of morphologic differentiation. These ducts have low proliferative index and accompanied by a vast decrease in proliferation of ERalpha-positive cells, including those that express c-neu. As such, c-neu has dual but opposing effects on ERalpha-dependent proliferation in mammary epithelial cells. Therefore, depending on the physiologic setting, ductal morphogenesis will be compromised both in the absence and overexpression of c-neu, thus explaining the paradox.