Abstract A11: N-Myc and STAT interactor (NMI): A regulator of developmental signaling and EMT

Abstract

Abstract The NMI protein associates with known key transcription factors such as Myc and STATs and serves as a critical regulatory co-factor that dictates specialized functions. While a physiological function for NMI is yet unknown, it has potential roles in pathologies ranging from viral infection to cancer. We will present pioneering work from our laboratory showing that NMI impacts two major developmental signaling pathways - TGFβ and Wnt pathways. EMT is one of the key phenomena underlying normal embryonic and organ development, with a vital role in metastatic progression. We discovered that the expression of NMI is significantly downregulated in metastatic breast tumors. We recapitulated this by stably silencing the expression of NMI in breast cancer cells. Abrogating NMI expression from epithelial-like breast cancer cells enabled cells to assume a mesenchymal-like phenotype. Detailed molecular and functional investigations revealed that this mesenchymal transition was facilitated by decreased STAT5 signaling that caused concomitant reduction in SMAD7 expression and manifestation of a TGFβ-driven EMT program. In contrast, breast cancer cells restored for NMI expression showed autophagic vacuoles and LC3 processing. We found that NMI expression restricts Wnt/β-catenin signaling by upregulation of the secreted Wnt inhibitor, DKK1. Thus NMI prompts activation of GSK3-β, a key kinase upstream of the TSC1/TSC2 complex. Inhibition of GSK3-ββin NMI expressing cells activated mTOR signaling and decreased the cells’ autophagic response. Autophagy is a determinant of cellular survival through dormancy and cytotoxic drug insult. Rapid progression of autophagy leads to cell death. In agreement with our molecular analyses, we determined that abrogation of NMI expression rendered cells resistant to cisplatin and doxorubicin. Our findings elicit interesting possibilities about the role of NMI in regulating EMT and autophagy. Evidence from our investigations strongly suggests that loss of NMI leading to aberrant activation of multiple developmental signaling pathways, may be a vital event in the progression of breast cancer characterized by reduced autophagy and stabilization of transcription factors that function as major drivers of EMT. Citation Format: Rajeev S. Samant, Hawley C. Pruitt, Brandon J. Metge, Lalita A. Shevde. N-Myc and STAT interactor (NMI): A regulator of developmental signaling and EMT. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A11.