Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, United States; Department of Pathology, Yale University, New Haven, United States
Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, United States; Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States
Ethan D Krop
Department of Pathology, Yale University, New Haven, United States; Department of Biosciences, Rice University,, Houston, United States
Yali Dou
Department of Pathology, University of Michigan, Ann Arbor, Ann Arbor, United States; Department of Medicine, Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, United States
Yale Cancer Center, Yale School of Medicine, New Haven, United States; Yale Cancer Biology Institute, Department of Pharmacology, Yale University, West Haven, United States
Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, United States; Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States
Thomas F Westbrook
Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, United States
Department of Pathology, Yale University, New Haven, United States; Yale Cancer Center, Yale School of Medicine, New Haven, United States; Yale Stem Cell Center, Yale School of Medicine, New Haven, United States; Department of Internal Medicine (Section of Medical Oncology), Yale School of Medicine,, New Haven, United States
Department of Pathology, Yale University, New Haven, United States; Yale Cancer Center, Yale School of Medicine, New Haven, United States; Yale Stem Cell Center, Yale School of Medicine, New Haven, United States; Yale Center for Immuno-Oncology, Yale School of Medicine, New Haven, United States
Metastatic breast cancer remains a major cause of cancer-related deaths in women, and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, a combination of WDR5 targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.
