Fig. 8

Summary: Mcl-1 confers protection of Her2-positive BC cells to hypoxia—therapeutic implications. Homodimerization of Her2 with Her2 or heterodimerization of Her2 with Her3 enhances phospho-inositol 3-kinase (PI3K)/AKT and RAS/mitogen-activated protein kinase (MAPK) pathways, which regulate BC cell proliferation, survival, and migration, as well as angiogenesis [60, 61]. The Her2 inhibitor trastuzumab [62] binds to the C-terminal portion of Her2. Another Her2 inhibitor, lapatinib [63], binds to the ATP binding site of Her2, but also Her1. Similar to siHER2, trastuzumab and lapatinib inhibit downstream signaling events, induce apoptosis, and inhibit proliferation of BC cells (red lines). Here we show a novel role for the antiapoptotic Bcl-2 family member Mcl-1 in Her2-positive BC cell adaptation to hypoxia. Specifically, our results show that Mcl-1 forms a protein complex with Her2 at the mitochondrial membrane and stabilizes Her2 by inhibiting its ubiquitination. Conversely, genetically (siMCL1) or pharmacologically (EU-5346) targeting Mcl-1 triggers ubiquitination and proteosomal degradation of Her2, thereby inducing apoptosis, and inhibiting proliferation and spheroid formation under hypoxic conditions. In addition, our results indicate the existence of a Mcl-1-dependent survival pathway in Her2-positive BC cells, which is independent of the Mcl-1–Her2 axis supporting the therapeutic benefit of combining Her2 (red lines) and Mcl-1 inhibitor (blue lines). Importantly, based on these findings, targeting Mcl-1 is also active in Her2-positive BC cells resistant to Her2 inhibitors, including a brain-primed Her2-positive cell line. Her human epidermal growth factor receptor, Mcl-1 myeloid cell leukemia-1. (Color figure online)