The majority of
cancers develop genetic and molecular strategies to resist conventional cytotoxic
therapies as well as escape from the host's immune surveillance. These events lead to
tumor persistence and spread through activation of the epithelial to mesenchymal transition (EMT) program and
metastasis. Expression profiling analysis has revealed various
tumor metastasis-inducing and
metastasis-suppressing genes that regulate the metastatic process and maintain the microenvironment of the
tumor cells. EMT in
cancer entails the molecular reprogramming and phenotypic changes that characterize the conversion of immobile
cancer epithelial cells to motile mesenchymal cells. A hallmark of EMT is the loss of
E-cadherin, the epithelial homotypic adhesion molecule, and gain of mesenchymal markers such as
vimentin and
fibronectin. The molecular mechanisms underlying the initiation of EMT consist, in part, in the constitutive activation of survival signaling pathways such as the nuclear factor (NF)-κB pathway. The NF-κB pathway has been implicated directly in the regulation of EMT and indirectly through the transcription and expression of several gene products that participate in the EMT cascade, such as Snail, the
metastasis-inducer and
E-cadherin suppressor
transcription factor. In turn, Snail represses the metastasis-suppressor gene product
Raf-kinase inhibitor protein (RKIP) that inhibits both the Raf-1/
MEK/ERK and NF-κB survival pathways implicated in EMT. Consequently,
tumor cells normally exhibit a dysregulated NF-κB/Snail/RKIP circuitry that is intimately involved in the initiation of EMT and maintenance of drug resistance. Additional deregulated gene products in this circuit, such as the
metastasis-suppressor
phosphatase and
tensin homologue (PTEN; repressed by Snail) and the putative-
metastasis inducer Yin Yang (YY) 1 (target of NF-κB) also have been associated in the regulation of EMT. We recently have investigated the direct role of YY1 in the regulation of EMT. This review discusses the molecular regulation of EMT in
cancer cells through the activity of the dysregulated NF-κB/Snail/ YY1/PTEN/RKIP circuitry. In addition, we propose YY1 as a potential novel prognostic
biomarker for EMT and a therapeutic target for both the prevention of
metastasis and the reversal of resistance.