海克素在乳腺癌细胞中作为雌激素受体 α 的共调节剂发挥作用。
Hakai acts as a coregulator of estrogen receptor alpha in breast cancer cells.
机构信息
Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Korea.
出版信息
Cancer Sci. 2010 Sep;101(9):2019-25. doi: 10.1111/j.1349-7006.2010.01636.x.
Abstract
Estrogen receptors play a key role in breast cancer development. One of the current therapeutic strategies for the treatment of estrogen receptor (ER)-α-positive breast cancers relies on the blockade of ERα transcriptional activity. In the present study, we characterized Hakai, originally characterized as an E-cadherin binding protein, as a strong blockade of ERα in breast cancer cells. We showed that Hakai inhibited the transcriptional activity of ERα by binding directly to ERα. The DNA-binding domain of ERα was found to be responsible for its interaction with Hakai. Hakai competed with ERα coactivators, such as steroid receptor coactivator-1 (SRC-1) and glucocoriticord receptor interacting protein-1 (GRIP-1), for the modulation of ERα transactivation, while its ubiquitin-ligase activity was not required. Further, overexpression of Hakai inhibited the proliferation and migration of breast cancer cells. Taken together, these results suggest that Hakai is a novel corepressor of ERα and may play a negative role in the development and progression of breast cancers.
摘要
雌激素受体在乳腺癌的发展中起着关键作用。目前治疗雌激素受体（ER）-α阳性乳腺癌的一种治疗策略依赖于阻断 ERα 的转录活性。在本研究中，我们将 Hakai 鉴定为一种 E-钙黏蛋白结合蛋白，其作为一种强有力的乳腺癌细胞中 ERα 的阻断剂。我们表明 Hakai 通过直接与 ERα 结合来抑制 ERα 的转录活性。发现 ERα 的 DNA 结合结构域负责与 Hakai 的相互作用。Hakai 与 ERα 共激活因子竞争，例如甾体激素受体共激活因子-1（SRC-1）和糖皮质激素受体相互作用蛋白-1（GRIP-1），以调节 ERα 的反式激活，而其泛素连接酶活性并非必需。此外，Hakai 的过表达抑制了乳腺癌细胞的增殖和迁移。综上所述，这些结果表明 Hakai 是 ERα 的新型核心抑制因子，可能在乳腺癌的发生和发展中发挥负作用。
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