Stack G, Kumar V, Green S, Ponglikitmongkol M, Berry M, Rio M C, Nunez A M, Roberts M, Koehl C, Bellocq P
Cancer Treat Res. 1988;40:185-206. doi: 10.1007/978-1-4613-1733-3_8.
The role of estrogen in the growth of human breast cancers has been investigated at two levels. First, we have studied the pS2 gene, whose transcription is stimulated by estrogen in the human breast cancer cell line, MCF-7. The pS2 gene product is a small, secreted polypeptide currently of unknown function, but with structural features similar to some growth factors. The expression of the pS2 gene has so far been detected only in MCF-7 cells and some breast cancer biopsies. Preliminary studies indicate that pS2 is a potential marker for hormone-dependent breast cancer. Ongoing studies will continue to focus on the implicated role of pS2 in the estrogen-mediated growth of breast cancers and its possible use as a marker for estrogen-dependent tumors. Second, we have analyzed the structure and function of the human ER. The receptor stimulates pS2 gene transcription by interacting with an ERE in the 5'-flanking region of that gene. A mutational analysis of the receptor protein has localized a DNA-binding domain, which determines target gene specificity, and a hormone-binding domain. These domains appear to be the only two regions of the receptor which are absolutely required for the transcription-activating function of the ER in transfection assays with reporter plasmids. The N-terminal region of the protein (regions A and B), which is necessary for increasing the efficiency of gene expression using the pS2 ERE, but not a vitellogenin ERE, may also play a role in transcription activation. Further progress in the characterization of the ER functional domains will require studies on target genes in a more physiological chromatin environment, as well as detailed physical analyses of receptor structure.
雌激素在人类乳腺癌生长中的作用已在两个层面上进行了研究。首先，我们研究了pS2基因，其转录在人类乳腺癌细胞系MCF - 7中受雌激素刺激。pS2基因产物是一种小的分泌型多肽，目前功能未知，但具有与某些生长因子相似的结构特征。到目前为止，pS2基因的表达仅在MCF - 7细胞和一些乳腺癌活检组织中检测到。初步研究表明，pS2是激素依赖性乳腺癌的一个潜在标志物。正在进行的研究将继续聚焦于pS2在雌激素介导的乳腺癌生长中的作用及其作为雌激素依赖性肿瘤标志物的可能用途。其次，我们分析了人类雌激素受体（ER）的结构和功能。该受体通过与该基因5'侧翼区域的雌激素反应元件（ERE）相互作用来刺激pS2基因转录。对受体蛋白的突变分析确定了一个决定靶基因特异性的DNA结合结构域和一个激素结合结构域。在使用报告质粒的转染实验中，这些结构域似乎是ER转录激活功能绝对必需的仅有的两个区域。该蛋白的N端区域（A和B区），对于使用pS2的ERE提高基因表达效率是必需的，但对卵黄生成素ERE则不是，它可能也在转录激活中发挥作用。ER功能结构域特征的进一步进展将需要在更生理的染色质环境中对靶基因进行研究，以及对受体结构进行详细的物理分析。
