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Nuclear Respiratory Factor 1 Acting as an Oncoprotein Drives Estrogen-Induced Breast Carcinogenesis

Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA
Research Service, Bruce W Carter VA Medical Center, 1201 NW 16th St, Miami, FL 33136, USA
Department of Pathology, Florida International University, Miami, FL 33199, USA
Author to whom correspondence should be addressed.
Cells 2018, 7(12), 234;
Received: 3 September 2018 / Revised: 7 November 2018 / Accepted: 18 November 2018 / Published: 27 November 2018
(This article belongs to the Special Issue Mitochondrial Metabolic Reprogramming and Nuclear Crosstalk in Cancer)
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. View Full-Text
Keywords: estrogen; breast cancer stem cell; NRF1; oncoprotein; re-programming estrogen; breast cancer stem cell; NRF1; oncoprotein; re-programming
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MDPI and ACS Style

Das, J.K.; Felty, Q.; Poppiti, R.; Jackson, R.M.; Roy, D. Nuclear Respiratory Factor 1 Acting as an Oncoprotein Drives Estrogen-Induced Breast Carcinogenesis. Cells 2018, 7, 234.

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