ER-α36-mediated rapid estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells.
ER-α36-mediated rapid estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells.
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DOI：
10.1371/journal.pone.0088034
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wang ZY
中科院分区：
文献类型：
--
作者：
Deng H;Zhang XT;Wang ML;Zheng HY;Liu LJ;Wang ZY
乳腺癌干细胞(BCSC)在乳腺癌的发生、复发和转移中起重要作用。然而，雌激素信号作为乳腺癌发生发展的重要信号通路，在调节BCSC中的作用还不是很清楚。此前，我们鉴定并克隆了雌激素受体α的变异体ER-α36，其相对分子质量为36 kDa。ER-α36缺乏66 kDa全长ER-α(ER-α66)的反式激活结构域AF-1和AF-2，并介导快速雌激素信号转导促进乳腺癌细胞的增殖。在本研究中，我们旨在探讨ER-α36介导的快速雌激素信号在ER阳性乳腺癌干/祖细胞生长调节中的作用及其机制。使用ER阳性的乳腺癌细胞MCF7和T47D以及ER-α36表达水平不同的突变体。通过肿瘤球体形成、流式细胞仪、间接免疫荧光染色和体内移植实验，观察雌激素对BCSC生长、自我更新、分化和移植瘤能力的影响。并通过Western-Blot分析对其作用机制进行了研究。我们发现，17-β-雌二醇(E_2-β)处理增加了ER阳性乳腺癌干/祖细胞的数量，而在ER-α36表达下调的细胞中却没有这样做。然而，强制表达重组ER-α36的细胞对E2β处理有强烈的反应，在体外增加了生长和体内的肿瘤种植效率。通过Akt/Gsk3β通路的快速雌激素信号参与了雌激素刺激的ER阳性乳腺癌干/祖细胞的生长。我们的结论是，ER-α36介导的快速雌激素信号在调节和维持ER阳性的乳腺癌干/祖细胞中起着重要作用。
The breast cancer stem cells (BCSC) play important roles in breast cancer occurrence, recurrence and metastasis. However, the role of estrogen signaling, a signaling pathway important in development and progression of breast cancer, in regulation of BCSC has not been well established. Previously, we identified and cloned a variant of estrogen receptor α, ER-α36, with a molecular weight of 36 kDa. ER-α36 lacks both transactivation domains AF-1 and AF-2 of the 66 kDa full-length ER-α (ER-α66) and mediates rapid estrogen signaling to promote proliferation of breast cancer cells. In this study, we aim to investigate the function and the underlying mechanism of ER-α36-mediated rapid estrogen signaling in growth regulation of the ER-positive breast cancer stem/progenitor cells. ER-positive breast cancer cells MCF7 and T47D as well as the variants with different levels of ER-α36 expression were used. The effects of estrogen on BCSC's abilities of growth, self-renewal, differentiation and tumor-seeding were examined using tumorsphere formation, flow cytometry, indirect immunofluorence staining and in vivo xenograft assays. The underlying mechanisms were also studied with Western-blot analysis. We found that 17-β-estradiol (E2β) treatment increased the population of ER-positive breast cancer stem/progenitor cells while failed to do so in the cells with knocked-down levels of ER-α36 expression. Cells with forced expression of recombinant ER-α36, however, responded strongly to E2β treatment by increasing growth in vitro and tumor-seeding efficiency in vivo. The rapid estrogen signaling via the AKT/GSK3β pathway is involved in estrogen-stimulated growth of ER-positive breast cancer stem/progenitor cells. We concluded that ER-α36-mediated rapid estrogen signaling plays an important role in regulation and maintenance of ER-positive breast cancer stem/progenitor cells.
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影响因子：
10.5
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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