Investigating whether constitutive death and compensatory survival signals e ist in HER2 overe pressing cells is of importance, as it may lead to the identification of a critical event in the HER2 net work that needs to be altered by current targeted thera pies, or that could be directly targeted without altering the rest of the network with great therapeutic benefit. An investigation of the roles played by the Bcl 2 family of proteins in the survival of HER2 overe pres sing cells may prove very useful to address this issue. This family of interacting proteins represents an inte grating node towards which converge numerous death and survival signals in mammalian cells, including these induced by oncogenic signals.
Anti apoptotic Bcl 2 homologues preserve mitochondrial integrity by oppos ing the activity of multi domain pro apoptotic Bcl 2 family members Ba and Bak, which display sequence conservation throughout three Bcl 2 homology domains, and that of their upstream effectors, the BH3 only proteins. This occurs essentially by physical interactions between anti and pro apoptotic members which allows the former to negatively control the activation, and the activity, of pro apoptotic Ba and Bak. Anti apoptotic Bcl 2 homologues control the sensitivity to conven tional pro apoptotic therapy of tumor cells. In certain instances, their e pression is necessary to maintain the survival of cancer cells, indicating that they may be required to counteract constitutive death signals. There is substantial evidence that the balance between anti and pro apoptotic proteins of the Bcl 2 family is biased in favor of survival proteins during breast carci nogenesis.
Most breast cancers arise from epithelial cells that e press Bcl 2, Bcl L and Mcl 1, and enhanced e pression of these proteins is almost system atically found in transformed mammary epithelial cells. Signaling pathways downstream of HER2 have numer ous anti apoptotic effects on Bcl 2 family members. In this study, we investigated whether and how the imbalance in favor of survival proteins of the Bcl 2 family, which is induced by the sustained activity of sig naling pathways downstream of HER2, contributes to survival maintenance in HER2 overe pressing breast cancer cells. We herein demonstrate that such cells undergo apoptosis upon depletion of Mcl 1, and that this Mcl 1 dependence GSK-3 is due to their constitutive e pression of the pro apoptotic protein Bim. The latter e pression is a direct consequence of oncogenic signal ing, as it is due to mTORC1 dependent e pression of c Myc, which occupies regions within the Bim promoter.