Abstract
Triple-negative breast cancer (TNBC) shows a higher malignant and poorer clinical outcome compared with other breast cancer subtypes. Albeit that chemotherapy is the first choice for TNBC treatment, rapid emergence of chemoresistance and variability of chemotherapeutic responses in TNBC patients call for novel therapeutic strategies. Here, we reported evidences highlighting that combination of BH3 mimetics and mTOR inhibitors could be a promising therapeutic strategy to improve TNBC treatment. Our results showed that combination of the BH3 mimetic ABT263 and typical mTOR inhibitors, BEZ235 or AZD8055, leads to efficient apoptosis in vitro. Tumor regression was significantly improved by combination therapy compared with either drug alone in the xenograft model. Further mechanistic investigations revealed that mTOR inhibitors induced the suppression of MCL-1; concomitantly, the expression level of PUMA was significantly upregulated in a FOXO3a-dependent manner. The specific changes of MCL-1 and PUMA facilitated the release of the apoptotic regulators, such as BIM, BAX, and BAK, to induce the activation of mitochondrial apoptotic pathway, thereby sensitizing the ABT263 activity in TNBC. Therefore, our findings provided evidences that mTOR inhibitors can enhance antitumor efficacy of BH3 mimetics via downregulating MCL-1 and upregulating PUMA in TNBC; it could be a promising therapeutic strategy to treat TNBC.
Highlights
Triple-negative breast cancer (TNBC), accounting for15–20% of breast cancers, is defined by lack of expressions of progesterone receptors, estrogen receptors (ERs), and human epidermal growth factor receptor-2 (HER2)[1]
The results showed that the expressions of MCL-1, BCL-XL, and BCL-2 were relatively high in TNBC cell lines (Fig. 1a), especially the MCL-1 level was quite high in most of the tested TNBC cell lines, suggesting that MCL-1 might be a key prosurvival factor in TNBC15
Many efforts were made based on chemotherapy, like neoadjuvant chemotherapy, and some benefits were shown in TNBC;[5,31] chemotherapy resistance invariably develops due to its heterogeneity[5]
Summary
Triple-negative breast cancer (TNBC), accounting for15–20% of breast cancers, is defined by lack of expressions of progesterone receptors, estrogen receptors (ERs), and human epidermal growth factor receptor-2 (HER2)[1]. Compared with other breast cancer subtypes, TNBC shows poorer outcome and higher lethality due to an aggressive clinical behavior and a high risk of relapse and metastasis[2]. Luminal-like breast cancers are sensitive to ER-targeted therapy and HER2-positive breast cancers can benefit from Trastuzumab treatment[3,4], TNBCs, whose first-line therapy is systematic conventional chemotherapy besides surgery or radiotherapy[5], has no effective targeted therapy in the clinical setting. Clinical investigations reported that only about 30% of patients suffering TNBC are sensitive to primary chemotherapy and display a pathologic complete response[1,5], patients with residual disease after chemotherapy. Li et al Cell Death and Disease (2018)9:137 show high recurrence and a low three-year overall survival rates[6]. It is urgent to develop new therapeutic strategies that targeting key molecules or signaling pathway members to treat TNBC, which is different from conventional chemotherapy
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