Department of Obstetrics and Gynecology, and CTRC, San Antonio, TX, USA.
J Steroid Biochem Mol Biol. 2010 Feb 28;118(4-5):211-8. doi: 10.1016/j.jsbmb.2009.09.009. Epub 2009 Sep 30.
Estradiol (E2), estrogen receptor (ER), ER-coregulators have been implicated in the development and progression of breast cancer. In situ E2 synthesis is implicated in tumor cell proliferation through autocrine or paracrine mechanisms, especially in post-menopausal women. Several recent studies demonstrated activity of aromatase P450 (Cyp19), a key enzyme that plays critical role in E2 synthesis in breast tumors. The mechanism by which tumors enhance aromatase expression is not completely understood. Recent studies from our laboratory suggested that PELP1 (Proline, Glutamic acid, Leucine rich Protein 1), a novel ER-coregulator, functions as a potential proto-oncogene and promotes tumor growth in nude mice models without exogenous E2 supplementation. In this study, we found that PELP1 deregulation contributes to increased expression of aromatase, local E2 synthesis and PELP1 cooperates with growth factor signaling components in the activation of aromatase. PELP1 deregulation uniquely up-regulated aromatase expression via activation of aromatase promoter I.3/II. Analysis of PELP1 driven mammary tumors in xenograft as well as in transgenic mouse models revealed increased aromatase expression. PELP1-mediated induction of aromatase requires functional Src and PI3K pathways. Chromatin immuno precipitation (ChIP) assays revealed that PELP1 is recruited to the Aro 1.3/II aromatase promoter. HER2 signaling enhances PELP1 recruitment to the aromatase promoter and PELP1 plays a critical role in HER2-mediated induction of aromatase expression. Mechanistic studies revealed that PELP1 interactions with orphan receptor ERRalpha, and histone demethylases play a role in the activation of aromatase promoter. Accordingly, ChIP analysis showed alterations in histone modifications at the aromatase promoter in the model cells that exhibit local E2 synthesis. Immunohistochemical analysis of breast tumor progression tissue arrays suggested that deregulation of aromatase expression occurs in advanced-stage and node-positive tumors, and that cooverexpression of PELP1 and aromatase occur in a sub set of tumors. Collectively, our results suggest that PELP1 regulation of aromatase represent a novel mechanism for in situ estrogen synthesis leading to tumor proliferation by autocrine loop and open a new avenue for ablating local aromatase activity in breast tumors.
雌二醇（E2）、雌激素受体（ER）和 ER 共调节剂已被牵涉到乳腺癌的发展和进展中。局部 E2 的合成通过自分泌或旁分泌机制促进肿瘤细胞增殖，特别是在绝经后妇女中。最近的几项研究表明，芳香化酶 P450（Cyp19）的活性，这种关键酶在乳腺癌肿瘤中起着关键作用。肿瘤增强芳香化酶表达的机制尚不完全清楚。我们实验室最近的研究表明，PELP1（脯氨酸、谷氨酸、亮氨酸丰富蛋白 1），一种新型的 ER 共调节剂，作为一种潜在的原癌基因，在没有外源性 E2 补充的情况下，在裸鼠模型中促进肿瘤生长。在这项研究中，我们发现 PELP1 失调导致芳香酶表达增加，局部 E2 合成增加，并且 PELP1 与生长因子信号成分合作激活芳香酶。PELP1 失调通过激活芳香酶启动子 I.3/II 独特地上调芳香酶表达。对异种移植和转基因小鼠模型中的 PELP1 驱动的乳腺肿瘤进行分析显示，芳香酶表达增加。PELP1 介导的芳香酶诱导需要功能性 Src 和 PI3K 途径。染色质免疫沉淀（ChIP）试验表明，PELP1 被募集到 Aro 1.3/II 芳香酶启动子。HER2 信号增强 PELP1 募集到芳香酶启动子，并且 PELP1 在 HER2 介导的芳香酶表达诱导中起关键作用。机制研究表明，PELP1 与孤儿受体 ERRalpha 和组蛋白去甲基酶的相互作用在芳香酶启动子的激活中起作用。因此，ChIP 分析显示在表现局部 E2 合成的模型细胞中，芳香酶启动子的组蛋白修饰发生改变。对乳腺肿瘤进展组织阵列的免疫组织化学分析表明，芳香酶表达的失调发生在晚期和淋巴结阳性肿瘤中，并且 PELP1 和芳香酶的共表达发生在一部分肿瘤中。总之，我们的结果表明，PELP1 对芳香酶的调节代表了一种新的机制，用于通过自分泌环导致局部雌激素合成导致肿瘤增殖，并为在乳腺肿瘤中消除局部芳香酶活性开辟了新途径。
