N-Myc Interactor: A Gatekeeper Of Malignant Progression

Metastasis is the most lethal attribute of cancer progression. It is becoming increasingly evident that epithelial-mesenchymal transition (EMT) is one of the critical events in the metastatic process of solid tumors. Thus, understanding the molecular signaling that negatively influences EMT is of high importance. Here, we present interesting findings about the novel involvement of N-Myc Interactor (NMI) in restricting EMT. We observed that NMI expression is significantly compromised in advanced breast malignancies. Restoring its expression restricts malignant activities of breast cancer cell lines in vivo and in vitro. Specifically, exogenous expression reduces invasive and migratory potential of tumor cells along with remarkable morphologic transition towards an epithelial appearance. In addition, several key EMT markers such as TWIST, MMP2, SNAI2 and ZEB2 were reduced along with a concomitant gain of epithelial markers such as E-cadherin and Keratin 18. Conversely, silencing NMI from an immortalized breast epithelial line rendered the cells more mesenchymal. Studies using a variety of additional epithelial cell lines consistently revealed that silencing NMI expression coincided with increased expression of both ZEB2 and SNAI2, while NMI overexpression resulted in decreased expression. These expression profile changes were accompanied with significant changes in cell morphology in both 2-dimensional and 3D culture systems. Thus expression of NMI appears to be necessary and sufficient for maintaining the epithelial phenotype. TGF-β signaling is one of the key signaling pathways that influence EMT. We observed that NMI negatively regulates SMAD driven transcription. We noticed that NMI is able to contribute to this regulation by positively regulating the expression of the inhibitory SMAD, SMAD7. Overall, our data strongly suggests that loss of NMI may be one of the pivotal events in deregulation of TGF-β/SMAD signaling in invasive breast cancers. This loss leads to increased expression of EMT-inducing transcription factors that drive tumor growth and EMT-dependent malignant progression. Citation Format: Rajeev S. Samant, Daniel J. Devine, Jack W. Rostas, Brandon J. Metge, Lalita A. Shevde. N-Myc interactor: A gatekeeper of malignant progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr C28.