An Isoform of C/EBPβ, LIP, Regulates Expression of the Chemokine Receptor CXCR4 and Modulates Breast Cancer Cell Migration

Abstract

Metastasis is the primary cause of death in cancer patients. CXCR4/CXCL12 chemokine axis provides directional cues for breast cancer cells to metastasize to specific organs. Despite their potential clinical importance, how CXCR4 expression in breast cancer cells is regulated at the molecular level is not well understood. We identified an isoform of C/EBPβ, liver-enriched inhibitory protein (LIP), as a previously unrecognized transcriptional regulator of CXCR4 in breast cancer cells. LIP up-regulated the transcription of CXCR4 through direct interaction with the CXCR4 promoter. The increase in CXCR4 mRNA was paralleled by an increased cell surface expression of the CXCR4, which in turn promoted CXCR4-mediated breast cancer cell migration. A significant positive correlation between LIP and CXCR4 expression was observed in stage III and IV human breast carcinoma specimens. Neuregulin 1 (or NRG1, hereafter referred to as heregulin) increased CXCR4 expression in breast cancer cells, and this coincided with increased LIP binding on the CXCR4 promoter. These findings may have important implications for understanding the molecular basis of CXCR4-mediated breast cancer cell metastasis and could potentially allow us to develop novel strategies to reduce morbidity and mortality in patients with metastatic breast cancer.