Abstract
We have previously shown nuclear respiratory factor 1 (NRF1)-mediated transcriptional programming of mitobiogenesis contributes to estrogen-induced breast cancer through modulating cell cycle progression. In this study, we report a new role of NRF1 that goes beyond that of programming mitobiogenesis. Specifically, we report a novel oncogenic function of NRF1 supporting its causative role in breast cancer development and progression. The gain of NRF1 and/or treatment with 17β-estradiol (E2) produced heterogeneous breast cancer stem cell (BCSC)-like subsets composed of more than 10 distinct cell sub-populations. Flow sorting combined with confocal imaging of markers for pluripotency, epithelial mesenchymal transition (EMT), and BCSCs phenotypically confirmed that the BCSC-like subset arise from cell re-programming. Thus, we determined the molecular actions of NRF1 on its target gene CXCR4 because of its known role in the acquisition of the BCSC-like subset through EMT. CXCR4 was activated by NRF1 in a redox-dependent manner during malignant transformation. An NRF1-induced BCSC-like subset was able to form xenograft tumors in vivo, while inhibiting transcription of CXCR4 prevented xenograft tumor growth. Consistent with our observation of NRF1-driven breast tumorigenesis in the experimental model, higher protein levels of NRF1 were also found in human breast cancer tissue specimens. This highly novel role of NRF1 in the stochastic acquisition of BCSC-like subsets and their progression to a malignant phenotype may open an entirely new research direction targeting NRF1 signaling in invasive breast cancer. Our discovery of targeting transcriptional activation of CXCR4 to inhibit NRF1-induced oncogenic transformation provides a mechanistic explanation for estrogen-dependent breast carcinogenesis and opens new avenues in strategic therapeutics to fight breast cancer.
Highlights
Nuclear respiratory factor 1 (NRF1) is widely recognized for regulating genes encoding mitochondrial biogenesis [1]
Estrogen treatment increases mitochondrial mass, the DNA-binding activity of NRF1, a regulator of TFAM, and the level of TFAM, and TFAM shRNA inhibits colony formation in E2-treated breast cancer cells. These findings suggest that NRF1-mediated transcriptional programming of mitobiogenesis contributes to estrogen-induced cell cycle progression [5,7,8] Meta-analysis of 18 published breast cancer microarray data showed that NRF1 is elevated in high-grade breast tumors [7]
We have shown that reactive oxygen species (ROS)-mediated activation of NRF1 is critical for the growth of estrogen-induced breast cancer cells and estrogen-induced malignant breast cell transformation [9,10]
Summary
Nuclear respiratory factor 1 (NRF1) is widely recognized for regulating genes encoding mitochondrial biogenesis [1]. The NRF1 motif is found on the promoters of genes regulating the cell cycle, chromatin structure, cell apoptosis, cell adhesion/invasion, DNA repair, DNA methylation and transcriptional repression signaling, and epithelial adherens junctions [2,3,4]. These findings suggest that NRF1 is a multifunctional. Estrogen treatment increases mitochondrial mass, the DNA-binding activity of NRF1, a regulator of TFAM, and the level of TFAM, and TFAM shRNA inhibits colony formation in E2-treated breast cancer cells. These findings suggest that NRF1-mediated transcriptional programming of mitobiogenesis contributes to estrogen-induced cell cycle progression [5,7,8] Meta-analysis of 18 published breast cancer microarray data showed that NRF1 is elevated in high-grade breast tumors [7]
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