Bulun Serdar E, Simpson Evan R
Department of Obstetric and Gynecology, Northwestern University, Chicago, IL 60611, USA.
Adv Exp Med Biol. 2008;630:112-32. doi: 10.1007/978-0-387-78818-0_8.
Estrogen has been positively linked to the pathogenesis and growth of three common women's cancers (breast, endometrium and ovary). A single gene encodes the key enzyme for estrogen biosynthesis named aromatase, inhibition of which effectively eliminates estrogen production in the entire body. Aromatase inhibitors successfully treat breast cancer, whereas their roles in endometrial and ovarian cancers are less dear. Ovary, testis, adipose tissue, skin, hypothalamus and placenta express aromatase normally, whereas breast, endometrial and ovarian cancers overexpress aromatase and produce local estrogen exerting paracrine and intracrine effects. Tissue specific promoters distributed over a 93 kilobase regulatory region upstream of a common coding region alternatively control aromatase expression. A distinct set of transcription factors regulates each promoter in a signaling pathway- and tissue-specific manner. In cancers ofbreast, endometrium and ovary, aromatase expression is primarly regulated by increased activity of the proximally located promoter 1.3/II region. Promoters I.3 and II lie 215 bp from each other and are coordinately stimulated by PGE2 via a cAMP-PKA-dependent pathway. In breast adipose fibroblasts exposed to PGE2 secreted by malignant epithelial cells, activation of PKC potentiates cAMP-PKA-dependent induction ofaromatase. Thus, inflammatory substances such as PGE2 may play important roles in inducing local production of estrogen that promotes tumor growth.
雌激素与三种常见的女性癌症（乳腺癌、子宫内膜癌和卵巢癌）的发病机制及生长呈正相关。一种单一基因编码雌激素生物合成的关键酶——芳香化酶，抑制该酶可有效消除全身的雌激素生成。芳香化酶抑制剂可成功治疗乳腺癌，但其在子宫内膜癌和卵巢癌中的作用尚不清楚。卵巢、睾丸、脂肪组织、皮肤、下丘脑和胎盘正常表达芳香化酶，而乳腺癌、子宫内膜癌和卵巢癌则过度表达芳香化酶并产生局部雌激素，发挥旁分泌和自分泌作用。分布在一个共同编码区上游93千碱基调控区域的组织特异性启动子交替控制芳香化酶的表达。一组独特的转录因子以信号通路和组织特异性的方式调节每个启动子。在乳腺癌、子宫内膜癌和卵巢癌中，芳香化酶的表达主要受近端启动子1.3/II区域活性增加的调控。启动子I.3和II彼此相距215 bp，并通过cAMP-PKA依赖途径受到前列腺素E2（PGE2）的协同刺激。在暴露于恶性上皮细胞分泌的PGE2的乳腺脂肪成纤维细胞中，蛋白激酶C（PKC）的激活增强了cAMP-PKA依赖的芳香化酶诱导作用。因此，诸如PGE2等炎症物质可能在诱导促进肿瘤生长的局部雌激素产生中发挥重要作用。
