Das Jayanta K, Felty Quentin, Poppiti Robert, Jackson Robert M, Roy Deodutta
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.
Cells. 2018 Nov 27;7(12):234. doi: 10.3390/cells7120234.
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.
我们之前已经表明，核呼吸因子1（NRF1）介导的线粒体生物合成转录编程通过调节细胞周期进程，促进雌激素诱导的乳腺癌发生。在本研究中，我们报道了NRF1的一个新作用，该作用超出了其对线粒体生物合成编程的作用。具体而言，我们报道了NRF1的一种新的致癌功能，支持其在乳腺癌发生和发展中的致病作用。NRF1的增加和/或用17β-雌二醇（E2）处理产生了由10多个不同细胞亚群组成的异质性乳腺癌干细胞（BCSC）样亚群。流式分选结合多能性、上皮-间质转化（EMT）和BCSC标志物的共聚焦成像，从表型上证实了BCSC样亚群源于细胞重编程。因此，由于其在通过EMT获得BCSC样亚群中的已知作用，我们确定了NRF1对其靶基因CXCR4的分子作用。在恶性转化过程中，CXCR4以氧化还原依赖的方式被NRF1激活。NRF1诱导的BCSC样亚群能够在体内形成异种移植瘤，而抑制CXCR4的转录可阻止异种移植瘤的生长。与我们在实验模型中观察到的NRF1驱动的乳腺肿瘤发生一致，在人乳腺癌组织标本中也发现了更高水平的NRF1蛋白。NRF1在随机获得BCSC样亚群及其向恶性表型进展中的这种全新作用，可能为侵袭性乳腺癌中靶向NRF1信号通路开辟一个全新的研究方向。我们发现靶向CXCR4的转录激活以抑制NRF1诱导的致癌转化，为雌激素依赖性乳腺癌发生提供了一个机理解释，并为抗击乳腺癌的战略治疗开辟了新途径。
