Aromatase expression and regulation in breast and endometrial cancer.
Aromatase expression and regulation in breast and endometrial cancer.
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DOI：
10.1530/jme-15-0310
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发表时间：
2016-07
影响因子：
3.5
通讯作者：
Bulun SE
中科院分区：
文献类型：
--
作者：
Zhao H;Zhou L;Shangguan AJ;Bulun SE
长期接触过量的雌激素会增加患乳腺癌和1型子宫内膜癌的风险。绝经前妇女的雌激素大部分由卵巢合成，而卵巢外皮下脂肪组织是绝经后雌激素的主要组织来源。雌激素及其代谢物可通过增加增殖和DNA损伤引起乳腺和子宫内膜细胞的增生和肿瘤转化。一些转基因小鼠模型已经产生，以帮助了解芳香化酶和雌激素在正常乳房和乳腺癌发展中的生理和病理生理作用。芳香化酶是雌激素产生的关键酶，由至少十个部分组织选择性和交替使用的启动子组成。这些启动子受不同的信号通路调控，通过募集各种转录因子到它们的顺式调控元件来控制芳香化酶的表达和雌激素的形成。芳香化酶启动子的使用从I.4到I.3/II的转变是乳腺癌恶性上皮细胞周围成纤维细胞过量雌激素产生的原因。针对这些不同的途径和/或转录因子来修饰芳香化酶活性可能会导致以组织特异性方式抑制雌激素产生的新型治疗方法的发展。
Long-term exposure to excess estrogen increases the risk of breast cancer and type 1 endometrial cancer. Most of the estrogen in premenopausal women is synthesized by the ovaries, while extraovarian subcutaneous adipose tissue is the predominant tissue source of estrogen after menopause. Estrogen and its metabolites can cause hyperproliferation and neoplastic transformation of breast and endometrial cells via increased proliferation and DNA damage. Several genetically modified mouse models have been generated to help understand the physiological and pathophysiological roles of aromatase and estrogen in the normal breast and in the development of breast cancers. Aromatase, the key enzyme for estrogen production, is comprised of at least ten partially tissue-selective and alternatively used promoters. These promoters are regulated by distinct signaling pathways to control aromatase expression and estrogen formation via recruitment of various transcription factors to their cis-regulatory elements. A shift in aromatase promoter use from I.4 to I.3/II is responsible for the excess estrogen production seen in fibroblasts surrounding malignant epithelial cells in breast cancers. Targeting these distinct pathways and/or transcription factors to modify aromatase activity may lead to the development of novel therapeutic remedies that inhibit estrogen production in a tissue-specific manner.