Targeting a Novel Signaling Network Against Lung Metastasis of Breast Cancer

During invasion and metastasis, breast cancer cells undergo various stresses including hypoxia and ER stress. These stresses induce expression of the Tribbles family proteins, which are kinase-like scaffold proteins and regulate multiple signaling pathways. Our preliminary study identified the Inhibitor of DNA Binding-1 (ID1) as a Tribbles-binding protein. ID1is one of the six most significant genes in the lung metastasis gene expression signature, and plays a key role in tumor re-initiation in metastatic loci. Association with Tribbles prevents ubiquitination of ID1 and consequently stabilizes this transcription regulator. In this proposal, we evaluate a hypothesis that stress-induced Tribbles in breast cancer cells render the intracellular signaling landscape favorable for metastasis. The following aims will be pursued: (1) Determine the effects of silencing Tribbles in migration, invasion and lung metastasis of human triple-negative breast cancer cells; (2) Identify proteins that are in complex with Trib1 or Trib3 in lung metastasis-prone breast cancer cells by tandem-affinity purification and LC-MS/MS; (3) Examine whether cell penetrating peptides encoding the MEK1-binding region of Tribbles can inhibit migration, invasion and lung metastasis of human triple-negative breast cancers. The integrated approach should provide a scientific foundation to establish the Tribblesmediated signaling network as a therapeutic target.