Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA.
1] Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA [2] Department of Surgery, University of South Alabama, Mobile, AL, USA.
Oncogene. 2014 May 15;33(20):2620-8. doi: 10.1038/onc.2013.215. Epub 2013 Jun 17.
Epithelial-mesenchymal transition is one of the critical cellular programs that facilitate the progression of breast cancer to an invasive disease. We have observed that the expression of N-myc interactor (NMI) decreases significantly during progression of breast cancer, specifically in invasive and metastatic stages. Recapitulation of this loss in breast cell lines with epithelial morphology (MCF10A (non-tumorigenic) and T47D (tumorigenic)) by silencing NMI expression causes mesenchymal-like morphological changes in 3D growth, accompanied by upregulation of SLUG and ZEB2 and increased invasive properties. Conversely, we found that restoring NMI expression attenuated the mesenchymal attributes of metastatic breast cancer cells, accompanied by distinctly circumscribed 3D growth with basement membrane deposition and decreased invasion. Further investigations into the downstream signaling modulated by NMI revealed that NMI expression negatively regulates SMAD signaling, which is a key regulator of cellular plasticity. We demonstrate that NMI blocks TGF-β/SMAD signaling via upregulation of SMAD7, a negative feedback regulator of the pathway. We also provide evidence that NMI activates STAT signaling, which negatively modulates TGF-β/SMAD signaling. Taken together, our findings suggest that loss of NMI during breast cancer progression could be one of the driving factors that enhance the invasive ability of breast cancer by aberrant activation of TGF-β/SMAD signaling.
上皮-间充质转化是促进乳腺癌进展为侵袭性疾病的关键细胞程序之一。我们观察到，N- myc 相互作用因子（NMI）的表达在乳腺癌的进展过程中显著降低，特别是在侵袭和转移阶段。通过沉默 NMI 表达，在具有上皮形态的乳腺细胞系（MCF10A（非致瘤性）和 T47D（致瘤性））中再现这种丢失，导致 3D 生长中的间充质样形态变化，同时上调 SLUG 和 ZEB2 并增加侵袭特性。相反，我们发现恢复 NMI 表达减弱了转移性乳腺癌细胞的间充质特征，同时伴随着基底膜沉积和侵袭性降低的明显界限分明的 3D 生长。对 NMI 调节的下游信号的进一步研究表明，NMI 表达负调控 SMAD 信号，SMAD 信号是细胞可塑性的关键调节剂。我们证明 NMI 通过上调 SMAD7（该途径的负反馈调节剂）来阻断 TGF-β/SMAD 信号。我们还提供了证据表明，NMI 激活 STAT 信号，从而负调控 TGF-β/SMAD 信号。总之，我们的研究结果表明，NMI 在乳腺癌进展过程中的丢失可能是通过异常激活 TGF-β/SMAD 信号增强乳腺癌侵袭能力的驱动因素之一。
