UBE2T upregulation underlies the metastasis-associated chemoresistance of breast cancer that can be reversed by BET inhibitors

Abstract Most primary breast cancers are sensitive to chemotherapy and some of them can achieve pathological complete response (pCR) by neoadjuvant chemotherapy. However, metastatic breast cancers are almost impossible to reach pCR with chemotherapy and thus are incurable diseases. The mechanisms of metastasis-associated chemoresistance remain poorly understood. Using paired primary and metastatic triple-negative breast cancer (TNBC) models, we identify that UBE2T is responsible for metastasis-associated chemoresistance by promoting PHLPP ubiquitination and AKT phosphorylation, enhancing tumor stemness in metastatic breast cancer. Overexpressed NFYA is the transcription factor that upregulates UBE2T expression. Analysis of clinical samples shows that the NFYA/UBE2T/p-AKT axis was highly activated in metastatic breast cancer. More importantly, bromodomain and extraterminal domain proteins (BET) inhibitors are found to significantly reduce UBE2T transcription, restoring the sensitivity of metastatic breast cancer to chemotherapy both in vitro and in vivo. These findings suggest that BET inhibitors could reverse the metastasis-associated chemoresistance by targeting aberrantly upregulated NFYA/UBE2T/p-AKT pathway in metastatic breast cancer, particularly in TNBC.