A mandatory role of nuclear PAK4-LIFR axis in breast-to-bone metastasis of ERα-positive breast cancer cells.

Abstract	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.
Authors	Yanshu Li, Hongyan Zhang, Yue Zhao, Chunyu Wang, Zhenguo Cheng, Lina Tang, Yunling Gao, Furong Liu, Jiabin Li, Yan Li, Yang Li, Nanxi Geng, Xue Rui, Yuee Teng, Yunpeng Liu, Liu Cao, Rakesh Kumar, Feng Jin, Feng Li
Journal	Oncogene (Oncogene) Vol. 38 Issue 6 Pg. 808-821 (02 2019) ISSN: 1476-5594 [Electronic] England
PMID	30177834 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Biomarkers, Tumor ESR1 protein, human Estrogen Receptor alpha LIFR protein, human Leukemia Inhibitory Factor Receptor alpha Subunit Neoplasm Proteins PAK4 protein, human p21-Activated Kinases
Topics	Animals Biomarkers, Tumor (genetics, metabolism) Bone Neoplasms (genetics, metabolism, pathology, secondary) Breast Neoplasms (genetics, metabolism, pathology) Cell Nucleus Drosophila melanogaster Estrogen Receptor alpha (genetics, metabolism) Female Humans Leukemia Inhibitory Factor Receptor alpha Subunit (genetics, metabolism) MCF-7 Cells Mice Mice, Inbred BALB C Neoplasm Invasiveness Neoplasm Metastasis Neoplasm Proteins (genetics, metabolism) p21-Activated Kinases (genetics, metabolism)

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