Department of Cell Biology, Key Laboratory of Cell Biology of Ministry of Public Health, and Key Laboratory of Medical Cell Biology of Ministry of Education, China Medical University, No. 77, Puhe Road, Shenyang North New Area, 110122, Shenyang, Liaoning, China.
Department of Surgical Oncology, The First Hospital of China Medical University, No. 155, North Nanjing Street, Heping District, 110001, Shenyang, Liaoning, China.
Oncogene. 2019 Feb;38(6):808-821. doi: 10.1038/s41388-018-0456-0. Epub 2018 Sep 3.
The mechanism of estrogen receptor alpha (ERα)-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 ERα-mediated transactivation in a 17β-estradiol (E2)-dependent manner and promotes PAK4-ERα axis-mediated bone metastasis by targeting leukemia inhibitory factor receptor (LIFR) in ERα-positive breast cancer. An evaluation of clinical breast cancer samples revealed that nPAK4 is linked to ERα expression and appears to be associated with a poor prognosis in bone metastatic breast cancer. PAK4 bound and co-translocated with ERα from the cytoplasm to the nucleus upon stimulation with E2. nPAK4 enhanced the invasive potential of ERα-positive breast cancer cells in vitro and promoted breast cancer metastasis in vivo. Mechanistically, nPAK4 promoted the metastasis of ERα-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 ERα-positive breast cancer bone metastasis.
雌激素受体 alpha（ERα）阳性乳腺癌相关骨转移的机制尚不清楚。本文报道核 p21 激活激酶 4（nPAK4）通过靶向 ERα 阳性乳腺癌中的白血病抑制因子受体（LIFR），以 17β-雌二醇（E2）依赖的方式成为 ERα 介导的反式激活的新型抑制剂，并促进 PAK4-ERα 轴介导的骨转移。对临床乳腺癌样本的评估表明，nPAK4 与 ERα 表达相关，似乎与骨转移乳腺癌的不良预后相关。E2 刺激后，PAK4 与 ERα 从细胞质结合并共转位到细胞核。nPAK4 增强了 ERα 阳性乳腺癌细胞在体外的侵袭潜能，并促进了体内乳腺癌转移。在机制上，nPAK4 通过靶向骨转移抑制因子 LIFR 促进 ERα 阳性乳腺癌细胞的转移。引人注目的是，PAK4 的核积累可能促进侵袭表型，突出了 nPAK4 作为 ERα 阳性乳腺癌骨转移的新型预测生物标志物。
