Bulun Serdar E, Lin Zhihong, Imir Gonca, Amin Sanober, Demura Masashi, Yilmaz Bertan, Martin Regina, Utsunomiya Hiroki, Thung Steven, Gurates Bilgin, Tamura Mitsutoshi, Langoi David, Deb Santanu
Division of Reproductive Biology Research, Department of Obstetric and Gynecology, Northwestern University, Chicago, IL 60611, USA.
Pharmacol Rev. 2005 Sep;57(3):359-83. doi: 10.1124/pr.57.3.6.
A single gene encodes the key enzyme for estrogen biosynthesis termed aromatase, inhibition of which effectively eliminates estrogen production. Aromatase inhibitors successfully treat breast cancer and endometriosis, whereas their roles in endometrial cancer, uterine fibroids, and aromatase excess syndrome are less clear. Ovary, testis, adipose tissue, skin, hypothalamus, and placenta express aromatase normally, whereas breast and endometrial cancers, endometriosis, and uterine fibroids overexpress aromatase and produce local estrogen that exerts 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. Three mechanisms are responsible for aromatase overexpression in a pathologic tissue versus its normal counterpart. First, cellular composition is altered to increase aromatase-expressing cell types that use distinct promoters (breast cancer). Second, molecular alterations in stromal cells favor binding of transcriptional enhancers versus inhibitors to a normally quiescent aromatase promoter and initiate transcription (breast/endometrial cancer, endometriosis, and uterine fibroids). Third, heterozygous mutations, which cause the aromatase coding region to lie adjacent to constitutively active cryptic promoters that normally transcribe other genes, result in excessive estrogen formation owing to the overexpression of aromatase in many tissues.
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雌激素的产生。芳香化酶抑制剂成功地治疗了乳腺癌和子宫内膜异位症，而它们在子宫内膜癌、子宫肌瘤和芳香化酶过剩综合征中的作用尚不清楚。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、子宫内膜异位症和子宫肌瘤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。病理组织中芳香化酶相对于其正常对应物的过表达有三种机制。首先，细胞组成发生改变，以增加使用不同启动子的芳香化酶表达细胞类型（乳腺癌）。其次，基质细胞中的分子改变有利于转录增强子而非抑制剂与正常静止的芳香化酶启动子结合并启动转录（乳腺癌/子宫内膜癌、子宫内膜异位症和子宫肌瘤）。第三，杂合突变导致芳香化酶编码区与通常转录其他基因的组成型活性隐蔽启动子相邻，由于许多组织中芳香化酶的过表达，导致雌激素过度形成。
