This division is in part due to their sensitivity to antihor monal therapy such as tamoxifen or an aromatase inhibi tor. The luminal A subtype carries the best prognosis, followed by luminal B. The third subtype is ER PR and HER2, which contains gene amplification for the ErbB 2 HER2 oncogene. The HER2 subtype represents 15% to 25% of breast cancers and is currently treated with trastuzumab selleck compound plus a taxane based chemotherapy. The HER2 subtype of breast cancer is associated Inhibitors,Modulators,Libraries with excel lent survival outcomes due to adjuvant trastuzumab ther apy, a humanized monoclonal antibody that targets the HER2 receptor. However, 30% to 60% of metastatic HER2 breast cancer are resistant to trastuzumab. The fourth subtype of breast cancer is the normal like sub type, which resembles normal mammary epithelial cells expressing genes associated with adipose tissue.

The fifth subtype represents 15% of breast cancers and is triple negative, and thus lacks expression of ER PR and HER2. Triple negative breast cancers carry the worst prognosis because of the lack of Inhibitors,Modulators,Libraries US Food and Drug Administra tion approved targeted therapies. Inhibitors,Modulators,Libraries Thus, there is an immediate need for the elucidation of novel targets to treat women with triple negative breast cancer and to increase these patients overall survival. Notch signaling has emerged as a target for the treat ment of breast cancer. In the mammalian system, there are four Notch receptors and five known ligands. Inhibitors,Modulators,Libraries Cell to cell contact is critical for the activation of Notch signaling, which subsequently enables the pathway to modulate genes involved in cell fate such as proliferation or differentiation.

Notch is processed in the trans Golgi apparatus, where it undergoes the first of three pro teolytic cleavages. The single polypeptide is cleaved by furin like convertase forming the mature Notch recep tor, which is a heterodimer consisting of Notch extracellu lar and Notch transmembrane. The receptor is trafficked Inhibitors,Modulators,Libraries to the plasma membrane, where it awaits engagement with its membrane associated ligand. Upon ligand receptor engagement, the second cleavage by a disintegrin and metalloproteases 10 and more 17 releases NEC to be endocytosed into the ligand expressing cell. Sub sequently, NTM is cleaved by the g secretase com plex, liberating the intracellular portion of Notch. NIC translocates to the nucleus and binds to CBF 1, a constitutive transcriptional repressor, displacing core pressors and recruiting coactivators such as Mastermind. Notch activates many genes associated with differ entiation and or survival, including, but not limited to, the HES and HEY family of basic helix loop helix transcrip tion factors, cyclin D1 and c Myc. The third and final cleavage step is critical for active Notch signaling.