However, further work is needed to define the mechanism of DIA induced apoptosis of breast cancer cells. BCL2 suppresses apoptosis via the phosphatase inhibitor intrinsic pathway, and thus regulation of BCL2 is a plausible mechanism for the anti apoptotic function of MYB in mammary carcinoma cells. Indeed we have shown here that BCL2, a known MYB target gene in other cell types, is directly regulated by MYB in breast cancer cells, and have iden tified multiple MBS within the BCL2 gene. Moreover we have shown that BCL2 is necessary for the ability of MYB to protect such cells against DIA induced apoptosis. A common role for MYB in multiple tissues and cancers As briefly reviewed in the Introduction, and Inhibitors,Modulators,Libraries more exten sively elsewhere, MYB is essential for the prolifera tion of multiple cancer and normal cell types, including haemopoietic, colonic and mammary epithelial.

Simi larly, Inhibitors,Modulators,Libraries with the data presented in this report, there is now strong evidence that MYB can antagonize differentiation in all three cell systems. MYB is also involved in vascu lar smooth muscle cell proliferation and there are reports of MYB down regulation during differentiation in this system too. Moreover, c myb expression in developing and adult mice has been characterized using in situ hybridization and correlated with stage specific differentiation and mitotic activity. MYB can also suppress apoptosis in the hematopoietic and colonic epithelial systems, and, as reported here, in mammary epithelial cells. Data in these systems and those presented Inhibitors,Modulators,Libraries here have implicated BCL2 as a common effector, although probably not the only one.

Whether the other MYB phenotypes of proliferation and differentiation suppression are mediated by com mon or specific factors needs to be elucidated. However, it is likely that some tissue specific factors are involved in effects on differentiation, and indeed this is supported by our recent data in the haemopoietic Inhibitors,Modulators,Libraries system. Targeting MYB in breast cancer As discussed above, our data imply that MYB is required in ER positive mam mary carcinoma cells for three key hallmarks of cancer continued Inhibitors,Modulators,Libraries proliferation, suppression of differentia tion, and resistance to apoptosis. This could potentially make MYB an excellent therapeutic target in breast can cer, particularly under conditions where MYB activity is limiting for one or more of these processes. The attrac tiveness of MYB as a target in this disease is reinforced by the fact Dovitinib that 60 to 70% of all human breast tumors express MYB. Treating tumors by inducing cancer cell differentiation has been discussed for some time, although an attractive concept, it has rarely proved to be an effective approach by itself.