Gutzman Jennifer H, Nikolai Sarah E, Rugowski Debra E, Watters Jyoti J, Schuler Linda A
Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706, USA.
Mol Endocrinol. 2005 Jul;19(7):1765-78. doi: 10.1210/me.2004-0339. Epub 2005 Mar 3.
Despite the important roles of both prolactin (PRL) and 17beta-estradiol (E2) in normal mammary development as well as in breast cancer, and coexpression of the estrogen receptor (ER) and PRL receptor in many mammary tumors, the interactions between PRL and E2 in breast cancer have not been well studied. The activating protein 1 (AP-1) transcription factor, a known regulator of processes essential for normal growth and development as well as carcinogenesis, is a potential site for cross-talk between these hormones in breast cancer cells. Here we demonstrate that PRL and E2 cooperatively enhance the activity of AP-1 in MCF-7-derived cells. In addition to the acute PRL-induced ERK1/2 activation, PRL and E2 also individually elicited delayed, sustained rises in levels of phosphorylated p38 and especially ERK1/2. Together, these hormones increased the dynamic phosphorylation of ERK1/2 and c-Fos, and induced c-fos promoter activity. Synergistic activation of the transcription factor, Elk-1, reflected the PRL-E2 interaction at ERK1/2 and is a likely mechanism for activation of the c-fos promoter via the serum response element. The enhanced AP-1 activity resulting from the interaction of these hormones may increase expression of many target genes that are critical for oncogenesis and may contribute to neoplastic progression.
尽管催乳素（PRL）和17β-雌二醇（E2）在正常乳腺发育以及乳腺癌中都发挥着重要作用，且雌激素受体（ER）和PRL受体在许多乳腺肿瘤中共同表达，但PRL与E2在乳腺癌中的相互作用尚未得到充分研究。活化蛋白1（AP-1）转录因子是正常生长发育以及致癌过程中重要过程的已知调节因子，是乳腺癌细胞中这些激素之间相互作用的潜在位点。在此我们证明，PRL和E2协同增强MCF-7衍生细胞中AP-1的活性。除了PRL急性诱导的ERK1/2激活外，PRL和E2还分别引起磷酸化p38尤其是ERK1/2水平的延迟、持续升高。这些激素共同增加了ERK1/2和c-Fos的动态磷酸化，并诱导了c-fos启动子活性。转录因子Elk-1的协同激活反映了PRL-E2在ERK1/2处的相互作用，并且是通过血清反应元件激活c-fos启动子的可能机制。这些激素相互作用导致的AP-1活性增强可能会增加许多对肿瘤发生至关重要的靶基因的表达，并可能促进肿瘤进展。
