The mammary gland represents a unique developmental system in which major developmental events occur after birth. Postnatal development of the mammary gland occurs in response to stimulation with various growth factors (epidermal growth factor, insulin like growth factor l, growth hormone, and prolactin), and the steroid hormones estrogen and progesterone. The proliferation and differentiation of mammary epithelial cells is not continuous, both rather occur in waves of proliferation followed by waves of programmed cell death. Programmed cell death, or apoptosis, occurs during puberty as the end buds regress and hollow ducts are formed, as well as during involution when massive numbers of mammary epithelial cells die and tissue remodeling occurs. PI hypothesize that suppression of apoptosis at either of these developmental points will result in developmental abnormalities, and eventually in mammary cancer. This hypothesis will be tested using transgenic mice. Investigators have expressed a constitutively activated form of the anti-apoptotic protein kinase Akt (Myr-Akt) in the mammary gland of transgenic mice and determine its effect upon mammary gland development. They will also develop transgenic mice that express a constitutively activated form of the prolactin receptor 'D178) in the mammary gland of mice. The Myr-Akt mice will test whether Akt is a central regulator of apoptosis in mammary epithelial cells. They hypothesize that Myr-Akt will delay involution but not induce tumors. Mice expressing the constitutively activated prolactin receptor will test whether this receptor can provide a mitogenic signal to mammary epithelial cells, as well as suppress apoptosis. We believe that the activated prolactin receptor will alter mammary gland development by inducing florid development in virgin mice. We also expect that it will induce mammary tumors. These transgenic mice will then be used to identify oncogenes and tumor suppressor genes that are able to cooperative with either Myr-Akt or the D178 deletion mutant of the prolactin receptor in inducing mammary cancer. These studies will provide new information about the effect of the prolactin receptor upon mammary epithelial cells, and whether suppression of apoptosis in Important in mammary carcinogenesis.
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