Mukherjee A, Amato P, Craig-Allred D, DeMayo F J, O'Malley B W, Lydon J P
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, 77030 Houston, USA.
Ernst Schering Found Symp Proc. 2007(1):55-76. doi: 10.1007/2789_2007_057.
The importance of the progesterone receptor (PR) in transducing the progestin signal is firmly established in female reproductive and mammary gland biology; however, the coregulators preferentially recruited by PR in these systems have yet to be comprehensively investigated. Using an innovative genetic approach, which ablates gene function specifically in murine cell-lineages that express PR, steroid receptor coactivator 2 (SRC-2, also known as TIF-2 or GRIP-1) was shown to exert potent coregulator properties in progestin-dependent responses in the uterus and mammary gland. Uterine cells positive for PR (but devoid of SRC-2) led to an early block in embryo implantation, a phenotype not shared by knockouts for SRC-1 or SRC-3. In the case of the mammary gland, progestin-dependent branching morphogenesis and alveologenesis failed to occur in the absence of SRC-2, thereby establishing a critical coactivator role for SRC-2 in cellular proliferative programs initiated by progestins in this tissue. Importantly, the recent detection of SRC-2 in both human endometrium and breast suggests that this coregulator may provide a new clinical target for the future management of female reproductive health and/or breast cancer.
孕酮受体（PR）在转导孕激素信号中的重要性已在女性生殖和乳腺生物学中得到确凿证实；然而，PR在这些系统中优先招募的共调节因子尚未得到全面研究。采用一种创新的遗传学方法，该方法可特异性地消除表达PR的小鼠细胞谱系中的基因功能，结果表明类固醇受体共激活因子2（SRC-2，也称为TIF-2或GRIP-1）在子宫和乳腺的孕激素依赖性反应中发挥强大的共调节因子特性。PR呈阳性（但缺乏SRC-2）的子宫细胞导致胚胎着床早期受阻，这一表型在SRC-1或SRC-3基因敲除小鼠中未出现。就乳腺而言，在缺乏SRC-2的情况下，孕激素依赖性的分支形态发生和腺泡形成无法发生，从而确立了SRC-2在该组织中由孕激素启动的细胞增殖程序中的关键共激活因子作用。重要的是，最近在人类子宫内膜和乳腺中均检测到SRC-2，这表明该共调节因子可能为未来女性生殖健康和/或乳腺癌的管理提供一个新的临床靶点。
