Thus, although ATF3 is clearly expressed throughout post-natal development in the basal cell compartment of mammary glands in BK5.ATF3 SAR131675 supply transgenic females, this overexpression by itself in not sufficient to produce tumors, nor to fully activate the Wnt/b-catenin pathway. The effects of ATF3 expression in other systems are strongly contextdependent, and can include both apoptosis and growth stimulation, oncogenesis and tumor suppression. The requirement for parity to induce mammary tumorigenesis in the current model suggests that during pregnancy, lactation and/or involution contextual changes occur that allow full Wnt/ b-catenin pathway activation to occur. Preliminary histopathological Afatinib analyses have revealed that at mid-lactation, lobulo-alveolar differentiation is incomplete in transgenic glands, and further studies of this process and of involution at both the histological and molecular levels are in progress. The SNAI2 and SNAI1 genes have recently been identified as direct transcriptional targets of ATF3 in human mammary cells, and the murine homologs, Snai2 and Snai1 are up-regulated in ATF3-induced mammary tumors. Multiple, bidirectional interactions between Wnt/b-catenin pathway activation and Snail have been identified previously. Snail interacts directly with nuclear b-catenin and indirectly through repression of E-cadherin to increase the transactivation capacity of b-catenin. Wnt pathway activation, on the other hand, up-regulates Snail activity by stabilizing nuclear Snail protein in an Axin2/GSK3b-mediated process. Thus, a direct transcriptional activation of Snail by ATF3 may also be important in activating and/or maintaining Wnt/b-catenin signaling in these tumors through a positive feedback loop. Global gene expression analyses of human breast tumors have identified an expression pattern consistent with up-regulation of the canonical Wnt/b-catenin pathway that associates with the basal-like tumor subclass. Since there is significant overlap between the basal-like subclass and clinically defined triple negative breast cancer, this implies that Wnt/b-catenin signaling is important in triple negative breast cancer, representing those breast cancers that have the worst prognosis and no effective treatment regimen. Importantly, Rosen��s laboratory has recently shown that activation of Wnt/b-catenin signaling is a hallmark of tumor-initiating cells in a mouse model. Thus we have reason to believe that further analysis of the BK5.ATF3 model, in which mammary tumors are clearly basal-like and exhibit activatedWnt/b-catenin signaling, may provide a better understanding of processes that are extremely important in human breast tumorigenesis.