It rises from above that signaling pathways that lead to the truly expression and the stability of Bim will actively con tribute to render Mcl 1 expression required for survival. Our finding that Bim expression can be detected in lysates that were prepared from 5 HER2 amplified tumors that had received no treatment indicate that such pathways are active in this malignancy. Mechan isms that regulate Inhibitors,Modulators,Libraries Bim transcription in particular might be effective, as suggested by the possible enrichment for some Bim transcripts in HER2 amplified tumors revealed by our investigation of publicly available expression data from breast cancer. Our finding that RAD001 negatively regulates Bim expression indicate that mTORC1, which plays an important oncogenic role in HER2 amplified tumors, might contribute to this expression.

The pro apoptotic role our data attribute to the mTOR pathway is somewhat reminiscent to that reported for its downstream kinase S6K in hepatocytes, where S6K contributes to Bim expression. Our data suggest that mTORC1 favors Bim expression by control ling the expression and the activity of c Myc, and that this transcription factor is involved Inhibitors,Modulators,Libraries is the constitutive expression of Bim in BT474 cells. The results of our ChIP assays indicate that RAD001 sensitive c Myc might be directly involved in the transcription of Bim in BT474 cells. As the mTOR pathway is frequently active in HER2 overexpressing breast cancers and regulates c Myc activity, our results imply that the corresponding tumor cells might frequently express constitutive Bim.

This constitute a molecular vulnerability that renders the sustained anti apoptotic activity of Mcl 1 necessary for survival. Thus, one promising approach for the treat ment of HER2 overexpressing breast cancers might be one that relies on the use of inhibitors of the anti apoptotic Inhibitors,Modulators,Libraries activity of Mcl 1. Conclusions Inhibitors,Modulators,Libraries Our work provides strong support to the notion that some tumor cells might depend upon a limited number of anti apoptotic Bcl 2 like proteins for their survival. It establishes that this Bcl 2L dependence Inhibitors,Modulators,Libraries extends to HER2 amplified tumors, and that, in these tumors, it relies, at least in part, references on the interconnected pathways that lead to pro apoptotic Bim and anti apop totic Mcl 1 expressions. This implies that current tar geted approaches need to influence the balance between Bim and Mcl 1 to efficiently affect cancer cell survival. It also implies that novel strategies that directly act upon this balance without interfering with the rest of the HER2 network are a promising alternative for the treatment of this disease.