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腾讯登录Oncogene：雌激素在乳腺癌发病过程中的关键角色
| 导读 | 近日，发表在国际杂志Oncogene上的一篇研究论文中，来自伊利诺伊大学的研究人员通过研究发现雌激素在乳腺癌发生过程中的神秘角色，相关研究为开发新型乳腺癌的靶向疗法及帮助医生进行选择性疗法治疗乳腺癌患者提供了很大帮助。 |
近日，发表在国际杂志Oncogene上的一篇研究论文中，来自伊利诺伊大学的研究人员通过研究发现雌激素在乳腺癌发生过程中的神秘角色，相关研究为开发新型乳腺癌的靶向疗法及帮助医生进行选择性疗法治疗乳腺癌患者提供了很大帮助。
雌激素可以预先激活未折叠蛋白质反应（UPR），这一通路可以保护细胞免于压力影响；UPR可以刺激分子伴侣的产生，而这些分子伴侣已经为细胞分裂和生长做好了准备工作，没有分子伴侣帮助细胞进行蛋白质的折叠和装配，癌细胞就不会进行分裂，因此长期以来分子伴侣也是研究人员所感兴趣的一种抗癌靶点。当细胞缺少足够的氧气和营养物质时，UPR的激活就可以作为对压力的一种正常反应，研究者Shapiro表示，这项研究揭示了雌激素在癌症病理学及发生过程中所扮演的角色，当雌激素结合其细胞上的受体时就会引发细胞中一系列的级联效应分子事件，其中一种事件就是当储存钙质不同的细胞膜间打开时，钙质就会流入细胞，这种信号就是激活UPR的路径，该信号也可以帮助研究人员理解细胞增殖的发生，而钙质本身就是一种细胞增殖的信号。
研究者表示，UPR同时也是细胞死亡的介导子，如果正常细胞暴露于过多压力中时，压力效应就会诱发细胞凋亡；然而在癌症中，由雌激素诱导的UPR的轻微激活就会钝化细胞死亡的路径，从而使的癌细胞可以生存下去，甚至是在抗癌药物的作用下癌细胞依然可以肆无忌惮。
文章中，研究者发现，在进行他莫昔芬治疗的雌激素受体阳性的乳腺癌患者中，机体UPR表达激活的患者的癌症复发率是其它个体的3.7倍，而在乳腺癌诊断后10年，那些高水平UPR基因表达的患者中只有15%的患者（治疗后）是无病状态的，而UPR基因表达水平最低的患者无病率高达80%。本文的研究对于研究人员后期开发新型乳腺癌靶向疗法将非常关键。（转化医学网360zhyx.com）
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Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer
Oncogene doi:10.1038/onc.2014.292
N Andruska, X Zheng, X Yang, W G Helferich and D J Shapiro
In response to cell stress, cancer cells often activate the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). Little was known about the potential role in cancer of a different mode of UPR activation, anticipatory activation of the UPR prior to accumulation of unfolded protein or cell stress. We show that estrogen, acting via estrogen receptor α (ERα), induces rapid anticipatory activation of the UPR, resulting in increased production of the antiapoptotic chaperone BiP/GRP78, preparing cancer cells for the increased protein production required for subsequent estrogen–ERα-induced cell proliferation. In ERα-containing cancer cells, the estrogen, 17β-estradiol (E2) activates the UPR through a phospholipase C γ (PLCγ)-mediated opening of EnR IP3R calcium channels, enabling passage of calcium from the lumen of the EnR into the cytosol. siRNA knockdown of ERα blocked the estrogen-mediated increase in cytosol calcium and UPR activation. Knockdown or inhibition of PLCγ, or of IP3R, strongly inhibited the estrogen-mediated increases in cytosol calcium, UPR activation and cell proliferation. E2-ERα activates all three arms of the UPR in breast and ovarian cancer cells in culture and in a mouse xenograft. Knockdown of ATF6α, which regulates UPR chaperones, blocked estrogen induction of BiP and strongly inhibited E2-ERα-stimulated cell proliferation. Mild and transient UPR activation by estrogen promotes an adaptive UPR response that protects cells against subsequent UPR-mediated apoptosis. Analysis of data from ERα+ breast cancers demonstrates elevated expression of a UPR gene signature that is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen therapy, reduced time to recurrence and poor survival. Thus, as an early component of the E2-ERα proliferation program, the mitogen estrogen, drives rapid anticipatory activation of the UPR. Anticipatory activation of the UPR is a new role for estrogens in cancer cell proliferation and resistance to therapy.
Oncogene doi:10.1038/onc.2014.292
N Andruska, X Zheng, X Yang, W G Helferich and D J Shapiro
In response to cell stress, cancer cells often activate the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). Little was known about the potential role in cancer of a different mode of UPR activation, anticipatory activation of the UPR prior to accumulation of unfolded protein or cell stress. We show that estrogen, acting via estrogen receptor α (ERα), induces rapid anticipatory activation of the UPR, resulting in increased production of the antiapoptotic chaperone BiP/GRP78, preparing cancer cells for the increased protein production required for subsequent estrogen–ERα-induced cell proliferation. In ERα-containing cancer cells, the estrogen, 17β-estradiol (E2) activates the UPR through a phospholipase C γ (PLCγ)-mediated opening of EnR IP3R calcium channels, enabling passage of calcium from the lumen of the EnR into the cytosol. siRNA knockdown of ERα blocked the estrogen-mediated increase in cytosol calcium and UPR activation. Knockdown or inhibition of PLCγ, or of IP3R, strongly inhibited the estrogen-mediated increases in cytosol calcium, UPR activation and cell proliferation. E2-ERα activates all three arms of the UPR in breast and ovarian cancer cells in culture and in a mouse xenograft. Knockdown of ATF6α, which regulates UPR chaperones, blocked estrogen induction of BiP and strongly inhibited E2-ERα-stimulated cell proliferation. Mild and transient UPR activation by estrogen promotes an adaptive UPR response that protects cells against subsequent UPR-mediated apoptosis. Analysis of data from ERα+ breast cancers demonstrates elevated expression of a UPR gene signature that is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen therapy, reduced time to recurrence and poor survival. Thus, as an early component of the E2-ERα proliferation program, the mitogen estrogen, drives rapid anticipatory activation of the UPR. Anticipatory activation of the UPR is a new role for estrogens in cancer cell proliferation and resistance to therapy.
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