Abstract
Triple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Here, we pursued a combinatorial therapeutic approach to enhance the activity of selinexor, the first-in-class XPO1 inhibitor, by miR-34a ectopic expression in human TNBC experimental models. Anti-proliferative activity induced by selinexor and miR-34a expression, singly and in combination, was evaluated by MTS assay and cell counting. The effect of treatments on survivin and apoptosis-related proteins was assessed by western blotting and ELISA. The antitumor and toxic effects of individual and combined treatments were evaluated on TNBC orthotopic xenografts in SCID mice. Selinexor consistently showed anti-proliferative activity, although to a variable extent, in the different TNBC cell lines and caused the impairment of survivin expression and intracellular distribution, accompanied by apoptosis induction. Consistent with in vitro data, the XPO1 inhibitor variably affected the growth of TNBC orthotopic xenografts. miR-34a cooperated with selinexor to reduce survivin expression and improved its anti-proliferative activity in TNBC cells. Most importantly, miR-34a expression markedly enhanced selinexor antitumor activity in the less sensitive TNBC xenograft model, in absence of toxicity. Our data form a solid foundation for promoting the use of a miR-34a-based approach to improve the therapeutic efficacy of selinexor in TNBC patients.
Highlights
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer (BC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), which accounts for 15–20% of all BC cases [1]. initially chemotherapy sensitive, TNBC displays high rates of local recurrence and distant metastasis [2]
Looking for a strategy aimed at improving the activity of selinexor in TNBC experimental models, in this study we investigated the effect exerted by the ectopic expression of miR-34a precursor (miR-34a), an onco-suppressive miRNA known to be down-regulated in different tumor types [17], including TNBC [18], and previously reported to target survivin [19,20,21], on the in vitro and in vivo activity profile of selinexor
Looking for a strategy aimed at improving the activity of selinexor in the poorly responsive TNBC model, we evaluated the effects of miR-34a ectopic expression on TNBC
Summary
Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer (BC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), which accounts for 15–20% of all BC cases [1]. initially chemotherapy sensitive, TNBC displays high rates of local recurrence and distant metastasis [2]. Based on the notion that altered localization of proteins, which highly affects their biological functions, is a common feature in cancer [3], the regulation of protein trafficking between the nucleus and cytoplasm has been recently regarded as a novel control point for therapeutic interventions [4,5]. In this context, exportin 1 (XPO1), the sole nuclear exporter for a variety of tumor suppressors, cell cycle regulators and growth promoting/anti-apoptotic proteins [6], was found to be over-expressed in several cancer types, including BC [7].
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