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

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.