Zhang J, Brewer S, Huang J, Williams T
Department of Molecular, Cellular, and Developmental Biology, Yale University, 266 Whitney Avenue, New Haven, CT 06520, USA.
Dev Biol. 2003 Apr 1;256(1):127-45. doi: 10.1016/s0012-1606(02)00119-7.
AP-2 transcription factors are key regulators of mouse embryonic development. Aberrant expression of these genes has also been linked to the progression of human breast cancer. Here, we have investigated the role of the AP-2 gene family in the postnatal maturation of the mouse mammary gland. Analysis of AP-2 RNA and protein levels demonstrates that these genes are expressed in the mammary glands of virgin and pregnant mice. Subsequently, AP-2 expression declines during lactation and then is reactivated during involution. The AP-2alpha and AP-2gamma proteins are localized in the ductal epithelium, as well as in the terminal end buds, suggesting that they may influence growth of the ductal network. We have tested this hypothesis by targeting AP-2alpha expression to the mouse mammary gland using the MMTV promoter. Our studies indicate that overexpression of AP-2alpha inhibits mammary gland growth and morphogenesis, and this coincides with a rise in PTHrP expression. Alveolar budding is severely curtailed in transgenic virgin mice, while lobuloalveolar development and functional differentiation are inhibited during pregnancy and lactation, respectively. Our studies strongly support a role for the AP-2 proteins in regulating the proliferation and differentiation of mammary gland epithelial cells in both mouse and human.
AP-2转录因子是小鼠胚胎发育的关键调节因子。这些基因的异常表达也与人类乳腺癌的进展有关。在此，我们研究了AP-2基因家族在小鼠乳腺出生后成熟过程中的作用。对AP-2 RNA和蛋白质水平的分析表明，这些基因在未孕和怀孕小鼠的乳腺中表达。随后，AP-2表达在哺乳期下降，然后在退化期重新激活。AP-2α和AP-2γ蛋白定位于导管上皮以及末端芽，表明它们可能影响导管网络的生长。我们通过使用MMTV启动子将AP-2α表达靶向小鼠乳腺来验证这一假设。我们的研究表明，AP-2α的过表达抑制乳腺生长和形态发生，这与甲状旁腺激素相关肽（PTHrP）表达的增加相吻合。在转基因未孕小鼠中，腺泡芽生严重减少，而在怀孕和哺乳期，小叶腺泡发育和功能分化分别受到抑制。我们的研究有力地支持了AP-2蛋白在调节小鼠和人类乳腺上皮细胞增殖和分化中的作用。
