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 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.
Highlights
Paclitaxel is a tubulin-targeting agents [1] commonly used in currently anti-cancer therapies
The data showed that correlations between the IC50 concentrations of paclitaxel and OTUD7B mRNA levels were marginal in the paclitaxel-untreated cells and significantly after treatment with paclitaxel in the tested triple-negative breast cancer (TNBC) cells (Figure 2A)
OTUD7B upregulation significantly predicts an unfavorable risk for cancer recurrence/metastasis and is associated with a poor response to paclitaxel-based chemotherapy in breast cancer patients
Summary
Paclitaxel is a tubulin-targeting agents [1] commonly used in currently anti-cancer therapies. The combination of paclitaxel with carboplatin was shown to significantly increase the proportion of 315 TNBC patients achieving a pathological complete response (pCR): this therapy produced a pCR rate of 59% compared with 38% pCR in patients who did not receive carboplatin [4]. A randomized phase II trial that enrolled 443 patients with stage II to III TNBC receiving standard paclitaxel therapy with or without carboplatin found that the combination resulted in a significantly higher pCR rate (54% vs 41%) [5]. These findings indicate that the majority of TNBC patients are likely insensitive to paclitaxel treatment. Since patients suffered from chemotherapy, identification of useful biomarkers for predicting pCR in TNBC patients receiving paclitaxel-based chemotherapies is urgently needed
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