Differential effects of estrogen-dependent transactivation vs. transrepression by the estrogen receptor on invasiveness of HER2 overexpressing breast cancer cells.
Differential effects of estrogen-dependent transactivation vs. transrepression by the estrogen receptor on invasiveness of HER2 overexpressing breast cancer cells.
复制标题
雌激素依赖性反式激活与雌激素受体反式抑制对 HER2 过表达乳腺癌细胞侵袭性的不同影响。
DOI：
10.1016/j.bbrc.2015.01.004
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发表时间：
2015
影响因子：
3.1
通讯作者：
Ratnam,Manohar
中科院分区：
文献类型：
--
作者：
Patki,Mugdha;Salazar,Marcelad'alincourt;Trumbly,Robert;Ratnam,Manohar
雌激素（E2）支持乳腺癌细胞生长，但抑制侵袭性，这两种作用都被抗雌激素拮抗。因此，抗雌激素治疗可能会增加由于HER 2扩增而具有内分泌抗性的雌激素受体（ER）+肿瘤细胞亚群的侵袭潜力。E2/ER的反式激活或反式阻遏可导致许多基因的上调和下调。抑制ER的反式激活功能足以抑制E2依赖性生长。然而，抑制E2依赖的反式激活与ER的反式阻遏对E2调节侵袭性的影响尚不清楚。在这里，我们剖析ER介导的反式激活和反式阻遏在调节ER+/HER 2+乳腺癌细胞的侵袭性E2的作用。敲除一般的ER共激活因子CBP和p300可阻止E2对其经典靶基因的激活，但不干扰E2抑制其直接靶基因的能力，已知这些靶基因支持侵袭性和肿瘤进展;对侵袭性或E2调节侵袭性的能力也没有影响。另一方面，ER的辅阻遏物结合位点突变体（L372 R）的过表达阻止了E2依赖的反式阻遏，但不阻止反式激活。突变的ER废除了E2抑制侵袭的能力。E2可以部分下调HER 2，但将HER 2敲低至E2调节水平以下并不影响侵袭性或E2调节侵袭性的能力，尽管它确实抑制生长。因此，在ER+/HER 2+细胞中，ER的E2依赖性反式阻遏而不是其反式激活功能对于调节侵袭性是至关重要的，并且这独立于E2对HER 2的调节。研究结果表明，选择性抑制剂的反式激活ER可能是更有益的，在减少肿瘤进展比传统的抗雌激素，也拮抗E2依赖的反式阻遏。
Estrogen (E2) supports breast cancer cell growth but suppresses invasiveness and both actions are antagonized by anti-estrogens. As a consequence, anti-estrogen treatment may increase the invasive potential of estrogen receptor (ER)+ tumor cell sub-populations that are endocrine resistant due to HER2 amplification. Either transactivation or transrepression by E2/ER could lead to both up- and down-regulation of many genes. Inhibition of the transactivation function of ER is adequate to inhibit E2-dependent growth. However, the impact of inhibiting E2-dependent transactivation vs. transrepression by ER on regulation of invasiveness by E2is less clear. Here we dissect the roles of ER-mediated transactivation and transrepression in the regulation of invasiveness of ER+/HER2+ breast cancer cells by E2. Knocking down the general ER co-activators CBP and p300 prevented activation by E2of its classical target genes but did not interfere with the ability of E2to repress its direct target genes known to support invasiveness and tumor progression; there was also no effect on invasiveness or the ability of E2to regulate invasiveness. On the other hand, overexpression of a co-repressor binding site mutant of ER (L372R) prevented E2-dependent transrepression but not transactivation. The mutant ER abrogated the ability of E2to suppress invasiveness. E2can partially down-regulate HER2 but knocking down HER2 below E2-regulated levels did not affect invasiveness or the ability of E2to regulate invasiveness, although it did inhibit growth. Therefore, in ER+/HER2+ cells, the E2-dependent transrepression by ER rather than its transactivation function is critical for regulation of invasiveness and this is independent of HER2 regulation by E2. The findings suggest that selective inhibitors of transactivation by ER may be more beneficial in reducing tumor progression than conventional anti-estrogens that also antagonize E2-dependent transrepression.