JunD and JunB Integrate Prostaglandin E2 Activation of Breast Cancer-Associated Proximal Aromatase Promoters
JunD and JunB Integrate Prostaglandin E2 Activation of Breast Cancer-Associated Proximal Aromatase Promoters
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DOI：
10.1210/me.2010-0368
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发表时间：
2011-05-01
影响因子：
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通讯作者：
Bulun, Serdar E.
中科院分区：
文献类型：
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作者：
Chen, Dong;Reierstad, Scott;Bulun, Serdar E.
芳香化酶是雌激素生物合成的关键酶。正常乳腺脂肪组织通过远端启动子I.4表达低水平的芳香化酶。肿瘤周围的乳腺脂肪组织表现出由近端芳香化酶启动子I.3/II控制的过度芳香化酶表达，导致局部高水平的雌激素和乳腺癌进展。在培养的人乳腺脂肪成纤维细胞（BAF）中，恶性乳腺上皮细胞分泌的前列腺素E-2（PGE（2））激活乳腺癌相关芳香化酶启动子I.3/II，但沉默启动子I.4。c-Jun N-末端激酶1和p38 α丝裂原活化蛋白激酶是PGE（2）激活芳香化酶启动子I.3/II所必需的;因此，我们研究了下游靶点c-Jun、JunB、JunD和转录激活因子2在PGE（2）介导的BAF芳香化酶表达调控中的作用。PGE（2）分别通过蛋白激酶A和蛋白激酶C诱导JunB和JunD蛋白表达。通过小干扰RNA敲低JunB或JunD显著降低PGE（2）诱导的总芳香化酶mRNA水平和酶活性。JunB基因敲除也使JunD基因表达消失。JunB刺激，而JunD抑制，芳香化酶启动子I.4活性。激活转录因子2敲低不影响启动子特异性或总芳香酶mRNA水平。c-Jun敲除增加了启动子I.4特异性和PGE（2）诱导的启动子I.3/II特异性芳香酶mRNA水平，导致PGE（2）诱导的总芳香酶mRNA水平和酶活性增强。JunD、c-Jun和JunB与PGE（2）诱导芳香酶启动子I.3/II所必需的CRE（-211/-199）结合。总之，JunD和c-Jun抑制芳香酶启动子I.4。JunD介导，而c-Jun调节，PGE（2）通过CRE（-211/-199）激活芳香酶启动子I.3/II。JunB还通过维持JunD表达来激活芳香酶启动子I.3/II。靶向JunD可以选择性地消除乳腺癌组织中芳香化酶的表达。（分子内分泌学25：767-775，2011）
Aromatase is the key enzyme in estrogen biosynthesis. Normal breast adipose tissue expresses low levels of aromatase via the distal promoter I.4. Breast adipose tissue surrounding a tumor exhibits excessive aromatase expression controlled by proximal aromatase promoters I.3/II, leading to high local levels of estrogen and breast cancer progression. Prostaglandin E-2 (PGE(2)) secreted by malignant breast epithelial cells activates breast cancer-associated aromatase promoters I.3/II, but silences promoter I.4, in cultured human breast adipose fibroblasts (BAF). The c-Jun N-terminal kinase 1 and p38 alpha mitogen activated protein kinases are necessary for PGE(2) activation of aromatase promoters I.3/II; thus, we examined the roles of downstream targets, c-Jun, JunB, JunD, and activating transcription factor 2, in PGE(2)-mediated regulation of aromatase expression in BAF. PGE(2) induced JunB and JunD protein expression through protein kinase A and protein kinase C, respectively. JunB or JunD knockdown by small interfering RNA markedly reduced PGE(2)-induced total aromatase mRNA level and enzyme activity via promoters I.3/II. JunB knockdown also abrogated JunD expression. JunB stimulated, whereas JunD inhibited, aromatase promoter I.4 activity. Activating transcription factor 2 knockdown did not affect promoter-specific or total aromatase mRNA levels. c-Jun knockdown increased promoter I.4-specific and PGE(2)-induced promoters I.3/II-specific aromatase mRNA levels, leading to enhanced PGE(2)-induced total aromatase mRNA level and enzyme activity. JunD, c-Jun, and JunB bound to a CRE(-211/-199) essential for PGE(2) induction of aromatase promoters I.3/II. Taken together, JunD and c-Jun repress aromatase promoter I.4. JunD mediates, whereas c-Jun modulates, PGE(2) activation of aromatase promoters I.3/II via CRE(-211/-199). JunB also activates aromatase promoters I.3/II by maintaining JunD expression. Targeting JunD may abolish aromatase expression selectively in breast cancer tissue. (Molecular Endocrinology 25: 767-775, 2011)