OTUD7B upregulation predicts a poor response to paclitaxel in patients with triple-negative breast cancer

Abstract

Paclitaxel is a first-line chemotherapeutic for patients with breast cancer, particularly triple-negative breast cancer (TNBC). Molecular markers for predicting pathologic responses to paclitaxel treatment is thus urgently needed since paclitaxel resistance is still a clinical issue in treating TNBCs. We investigated the transcriptional profiling of consensus genes in HCC38 (paclitaxel-sensitive) and MDA-MB436 (paclitaxel-resistant) TNBC cells post-treatment with paclitaxel. We found that OTUD7B was downregulated in HCC38 but upregulated in MDA-MB436 cells after paclitaxel treatment at cytotoxic concentrations. Moreover, our data showed that OTUD7B expression causally correlated with IC₅₀ of paclitaxel in a panel of TNBC cell lines. Moreover, we found that OTUD7B upregulation was significantly detected in primary breast cancer tissues compared to normal breast tissues but inversely correlated with tumor growth in TNBC cells. Besides, the increased levels of OTUD7B transcript appeared to causally associate with invasive and metastatic potentials in TNBC cells. In assessments of recurrence/metastasis-free survival probability, high-levels of OTUD7B transcripts strongly predicted a poor prognosis and unfavorable response to paclitaxel-based chemotherapy in patients with TNBCs. In silico analysis suggested that OTUD7B regulation, probably owing to miR-1180 downregulation, may negatively regulate the NF-κB-Lin28 axis which in turn triggers Let-7 microRNA-mediated caspase-3 downregulation, thereby conferring paclitaxel resistance in TNBCs. These findings suggest that OTUD7B may be a useful biomarker for predicting the anti-cancer effectiveness of paclitaxel and could serve as a new drug target for enhancing the canceridal efficiency of paclitaxel against TNBCs.