Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Endocrinology. 2012 Jun;153(6):2701-13. doi: 10.1210/en.2011-1761. Epub 2012 Apr 16.
Aromatase is essential for estrogen production and is the target of aromatase inhibitors, the most effective endocrine treatment for postmenopausal breast cancer. Peripheral tissues in women, including the breast, express aromatase via alternative promoters. Female mice lack the promoters that drive aromatase expression in peripheral tissues; thus, we generated a transgenic humanized aromatase (Arom(hum)) mouse line containing a single copy of the human aromatase gene to study the link between aromatase expression in mammary adipose tissue and breast pathology. Arom(hum) mice expressed human aromatase, driven by the proximal human promoters II and I.3 and the distal promoter I.4, in breast adipose fibroblasts and myoepithelial cells. Estrogen levels in the breast tissue of Arom(hum) mice were higher than in wild-type mice, whereas circulating levels were similar. Arom(hum) mice exhibited accelerated mammary duct elongation at puberty and an increased incidence of lobuloalveolar breast hyperplasia associated with increased signal transducer and activator of transcription-5 phosphorylation at 24 and 64 wk. Hyperplastic epithelial cells showed remarkably increased proliferative activity. Thus, we demonstrated that the human aromatase gene can be expressed via its native promoters in a wide variety of mouse tissues and in a distribution pattern nearly identical to that of humans. Locally increased tissue levels, but not circulating levels, of estrogen appeared to exert hyperplastic effects on the mammary gland. This novel mouse model will be valuable for developing tissue-specific aromatase inhibition strategies.
芳香酶对于雌激素的产生至关重要，是芳香酶抑制剂的作用靶点，而芳香酶抑制剂是治疗绝经后乳腺癌最有效的内分泌治疗方法。女性的外周组织，包括乳房，通过替代启动子表达芳香酶。雌性小鼠缺乏驱动外周组织中芳香酶表达的启动子；因此，我们生成了一种转基因人源化芳香酶（Arom(hum)）小鼠品系，该品系含有一个人芳香酶基因的单拷贝，用于研究乳腺脂肪组织中芳香酶表达与乳房病理学之间的联系。Arom(hum) 小鼠在乳腺脂肪成纤维细胞和肌上皮细胞中表达人类芳香酶，由近端人启动子 II 和 I.3 以及远端启动子 I.4 驱动。Arom(hum) 小鼠的乳腺组织中的雌激素水平高于野生型小鼠，而循环水平相似。Arom(hum) 小鼠在青春期表现出乳腺导管伸长加速，并且在 24 和 64 周时与转录激活因子 5 磷酸化增加相关的小叶腺泡乳腺增生的发生率增加。增生的上皮细胞表现出明显增加的增殖活性。因此，我们证明了人芳香酶基因可以通过其天然启动子在多种小鼠组织中表达，并且表达模式与人类非常相似。局部组织水平而非循环水平升高的雌激素似乎对乳腺发挥了增生作用。这种新型小鼠模型将有助于开发组织特异性芳香酶抑制策略。
