A mandatory role of nuclear PAK4-LIFR axis in breast-to-bone metastasis of ERα-positive breast cancer cells
A mandatory role of nuclear PAK4-LIFR axis in breast-to-bone metastasis of ERα-positive breast cancer cells
复制标题
核 PAK4-LIFR 轴在 ERα 阳性乳腺癌细胞乳腺至骨转移中的强制性作用。
DOI：
10.1038/s41388-018-0456-0
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发表时间：
2019-02-07
期刊：
影响因子：
8
通讯作者：
Li, Feng
中科院分区：
文献类型：
--
作者：
Li, Yanshu;Zhang, Hongyan;Li, Feng
雌激素受体α（ER α）阳性乳腺癌相关骨转移的机制知之甚少。在这篇文章中，我们报告说，核p21激活激酶4（nPAK 4）是一种新的阻遏ER α介导的反式激活的17 β-雌二醇（E2）依赖的方式，并促进PAK 4-ER α轴介导的骨转移靶向白血病抑制因子受体（LIFR）在ER α阳性乳腺癌。对临床乳腺癌样本的评估显示，nPAK 4与ER α表达相关，似乎与骨转移性乳腺癌的预后不良相关。PAK 4结合并与ER α从细胞质共易位到细胞核后，与E2的刺激。nPAK 4在体外增强ER α阳性乳腺癌细胞的侵袭潜力，并在体内促进乳腺癌转移。从机制上讲，nPAK 4通过靶向骨转移抑制因子LIFR促进ER α阳性乳腺癌细胞的转移。引人注目的是，PAK 4的核积累可能促进侵袭性表型，突出nPAK 4作为ER α阳性乳腺癌骨转移的新型预测生物标志物。
The mechanism of estrogen receptor alpha (ER alpha)-positive breast cancer-associated bone metastasis is poorly understood. In this article, we report that nuclear p21-activated kinase 4 (nPAK4) is a novel repressor of ER alpha-mediated transactivation in a 17 beta-estradiol (E2)-dependent manner and promotes PAK4-ER alpha axis-mediated bone metastasis by targeting leukemia inhibitory factor receptor (LIFR) in ER alpha-positive breast cancer. An evaluation of clinical breast cancer samples revealed that nPAK4 is linked to ERa expression and appears to be associated with a poor prognosis in bone metastatic breast cancer. PAK4 bound and co-translocated with ERa from the cytoplasm to the nucleus upon stimulation with E2. nPAK4 enhanced the invasive potential of ER alpha-positive breast cancer cells in vitro and promoted breast cancer metastasis in vivo. Mechanistically, nPAK4 promoted the metastasis of ER alpha-positive breast cancer cells by targeting LIFR, a bone metastasis suppressor. Strikingly, the nuclear accumulation of PAK4 might promote aggressive phenotypes, highlighting nPAK4 as a novel predictive biomarker for ER alpha-positive breast cancer bone metastasis.