UC San Diego

The ability of cancer cells to successfully metastasize depends on a myriad of factors that allow cells to leave their tumor of origin, travel within the body and successfully establish themselves in remote locations. Recent evidence suggests that cancer cells activate a conserved developmental program termed Epithelial Mesenchymal Transition (EMT) to facilitate their metastatic dissemination [1]. EMT is activated during development in epithelial cells to facilitate their movement and survival enabling the formation of new tissues and organs [2]. One of the first and most important steps in EMT progression is the loss of cell- cell adhesion. E-cadherin, a key mediator of cell-cell adhesion [3], has been shown to be directly and indirectly downregulated via many transcription factors expressed during EMT, these include Twist1 [4], Twist2 [5], ZEB1 [6], ZEB2 [7], Snail1 [8] and Snail2 [9]. In cancer, E-cadherin loss is associated with increased invasiveness [10]. It remains largely unknown however, whether transcription factors induced after EMT function independently or in concert to inhibit E-cadherin expression and promote EMT and metastasis. Twist1 is a basic-helix-loop helix transcription factor and a potent activator of EMT [11]. Twist1 was found to be necessary for the metastatic spread of highly invasive mouse mammary epithelial cells in a mouse model of breast cancer [11]. Additionally, it has been shown to correlate with invasiveness in many cancers [12], [13], [14], [15]. My studies were aimed at determining how Twist1 downregulates E-cadherin expression and promotes metastasis. I show that the Snail2 zinc- finger transcription factor is a direct transcriptional target of Twist1 and a vital downstream mediator of Twist1 -induced E-cadherin suppression and EMT. Furthermore, my studies indicate that Snail2 is essential for the metastatic spread of breast cancer cells to the lung in a mouse mammary tumor model and that Snail2 and Twist1 expression are highly correlated in a large number of breast cancer clinical samples. Overall, my results demonstrate an important conserved relationship between Twist1 and Snail2 in the regulation of cell-cell adhesion and EMT. This important relationship also appears to be exploited by cancer cells during cancer progression