Functional Roles of Multiple Feedback Loops in Extracellular Signal-Regulated Kinase and Wnt Signaling Pathways That Regulate Epithelial-Mesenchymal Transition

Abstract

Epithelial-mesenchymal transition (EMT) is a key event in the generation of invasive tumor cells. A hallmark of EMT is the repression of E-cadherin expression, which is regulated by various signal transduction pathways including extracellular signal-regulated kinase (ERK) and Wnt. These pathways are highly interconnected via multiple coupled feedback loops (CFL). As the function of such coupled feedback regulations is difficult to analyze experimentally, we used a systems biology approach where computational models were designed to predict biological effects that result from the complex interplay of CFLs. Using epidermal growth factor (EGF) and Wnt as input and E-cadherin transcriptional regulation as output, we established an ordinary differential equation model of the ERK and Wnt signaling network containing six feedback links and used extensive computer simulations to analyze the effects of these feedback links in isolation and different combinations. The results show that the feedbacks can generate a rich dynamic behavior leading to various dose-response patterns and have a decisive role in determining network responses to EGF and Wnt. In particular, we made two important findings: first, that coupled positive feedback loops composed of phosphorylation of Raf kinase inhibitor RKIP by ERK and transcriptional repression of RKIP by Snail have an essential role in causing a switch-like behavior of E-cadherin expression; and second, that RKIP expression inhibits EMT progression by preventing E-cadherin suppression. Taken together, our findings provide us with a system-level understanding of how RKIP can regulate EMT progression and may explain why RKIP is downregulated in so many metastatic cancer cells. Cancer Res; 70(17); 6715-24. ©2010 AACR.

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

“…Markers of EMT may have clinical value for patient preselection for trials using dasatinib. In addition, Wnt-signaling pathways regulate EMT and may contribute to tumor cell invasion (56). Mutations in the Wnt/β-catenin pathway (CTNNB1, APC, and WISP3) occur frequently (52%) in metaplastic breast cancer, suggesting that deregulated Wnt/β-catenin pathway in these tumors may be a viable therapeutic target (27).…”

Hepatitis B virus X protein represses miRNA-148a to enhance tumorigenesis

“…EMT is an important step toward tumor invasion and metastasis. EMT can be induced by a variety of different molecules and pathways, including AKT (42), ERK (43,44), and mTOR signaling (45)(46)(47), all of which are commonly deregulated in human cancers (5,48,49). Since miR-148a and HPIP are upstream regulators of AKT, ERK, and mTOR signaling, we believe that miR-148a and HPIP are critical regulators of EMT.…”

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis

“…62 The Matrix2 metagene included genes associated with the AP-1 transcription factor network (FOS, EGR1, FABP4, DUSP1), the EGR receptor signaling pathway (FOS, DUSP1, EGR1), the Wnt or ALK signaling pathway (CAV1), the MAPK signaling pathway (FOS, DUSP1) or Trk receptor signaling mediated by the MAPK pathway (FOS, EGR1), the mTOR signaling pathway (IGF1), the PPAR signaling pathway (ADIPOQ, CD36, FABP4), and androgen-mediated signaling (FOS, EGR1). These pathways may contribute to cell motility and tumor cell invasion 63 and play a prominent role in epithelial-mesenchymal transition (EMT) and in stem cells. These metagenes are strongly expressed in mesenchymal cells and metaplastic breast cancers.…”