A Genome-wide siRNA Screen Identifies Proteasome Addiction as a Vulnerability of Basal-like Triple-Negative Breast Cancer Cells
Menée à l'aide de modèles murins de cancer du sein "basal-like" triplement négatif, cette étude évalue l'intérêt de l'inhibition du protéasome pour réduire la croissance tumorale et prévenir le processus métastatique
Basal-like triple-negative breast cancers (TNBCs) have poor prognosis. To identify basal-like TNBC dependencies, a genome-wide siRNA lethality screen compared two human breast epithelial cell lines transformed with the same genes: basal-like BPLER and myoepithelial HMLER. Expression of the screen s 154 BPLER dependency genes correlated with poor prognosis in breast, but not lung or colon, cancer. Proteasome genes were overrepresented hits. Basal-like TNBC lines were selectively sensitive to proteasome inhibitor drugs relative to normal epithelial, luminal, and mesenchymal TNBC lines. Proteasome inhibition reduced growth of established basal-like TNBC tumors in mice and blocked tumor-initiating cell function and macrometastasis. Proteasome addiction in basal-like TNBCs was mediated by NOXA and linked to MCL-1 dependence. "Basal-like TNBC cell lines are addicted to the proteasome and MCL-1 "Proteasome inhibition blocks T-IC functions in basal-like TNBCs "Proteasome addiction in these cells is mediated by NOXA and linked to MCL-1 "Proteasome inhibitors inhibit basal-like tumor growth and metastasis in mice