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  • br Conflict of interest statement

    2019-05-18


    Conflict of interest statement
    Acknowledgments The authors would like to thank Dr. Bjørn Naume, and Dr. Erik Løkkevik from the Department of Clinical Oncology, the Norwegian Radium Hospital for their helpful comments. This study was supported by grants from the Norwegian Radium Hospital Foundation, the Norwegian Cancer Society and the Regional Health Authority of South-Eastern Norway.
    Introduction Breast cancer is the most prevalent malignancy in women, and the occurrence of bone metastases is a common long-term complication of this disease [1]. The pathophysiology of bone metastases is complex and a number of steps have to be surpassed by the cancer cell to successfully establish a metastatic lesion, including the adhesion of cancer Strengths at their metastatic site [2]. Bisphosphonates represent a standard therapy for patients with malignant bone lesions [3]. In addition to their established anti-resorptive effects, direct effects of amino-bisphosphonates on tumor biology have been proposed [4]. Established in vitro and in vivo effects of bisphosphonates on cancer cells include an induction of apoptosis, inhibition of proliferation, migration and invasion as well as anti-angiogenic effects [4–6]. In contrast to first generation bisphosphonates, which act by forming toxic ATP analogs, amino-bisphosphonates are inhibitors of the mevalonate pathway that block the farnesyl pyrophosphate (FPP) synthase [7]. FPP synthase inhibition leads to a decreased formation of isoprenoid lipids such as FPP and geranylgeranyl pyrophosphate (GGPP) and thereby impairs posttranslational protein prenylation [8]. In fact, many of the observed anti-tumor effects of bisphosphonates have been proposed to be mediated by inhibited protein geranylgeranylation [9]. Statins are the second major class of clinically approved compounds that act by mevalonate pathway inhibition [10]. Statins are widely used for their cholesterol-lowering effects, but have also been associated with potential direct anticancer effects [11]. Cancer cell adhesion is an important step of the metastatic cascade that is essential for the cancer to establish persistence at the site of metastasis. Mevalonate pathway inhibition may impair the adhesive abilities of circulating cancer cells and thereby impact their metastatic potential. Indeed, anti-adhesive effects of bisphosphonates have been described for several cell types, including breast cancer and HUVEC [12,13], but the underlying molecular mechanisms have not been studied in detail. In this study we investigate the effects of zoledronic acid on integrin mediated adhesion of breast cancer cells in the context of mevalonate pathway inhibition.
    Materials and methods
    Results
    Discussion The adhesion of disseminated cancer cells to their target structure is an essential step of the metastatic process. Both bisphosphonates and statins have been discussed for their direct anti-tumor effects [16,17]. Here, we assessed the influence of zoledronic acid and atorvastatin on the adhesion of two ER-negative breast cancer cell lines to extracellular matrix proteins. While these agents are primarily used for divergent indications, namely anti-resorptive therapy and cholesterol reduction, they have a common target by inhibiting the mevalonate pathway and a considerable overlap regarding preclinical anti-tumor activity has been noted [5,18]. Anti-adhesive effects of bisphosphonates in breast cancer have been previously described [19], but the role of the mevalonate pathway in this context has not been described in detail. Prenylation processes are important for the biological activity of numerous cellular signal transduction proteins. By blocking the mevalonate pathway both statins and nitrogen-containing bisphosphonates impair farnesylation and geranylation. In this study, we show that the observed anti-adhesive effects of bisphosphonates are directly mediated by an inhibition of post-translational geranylgeranylation as the effects are fully reversed in the presence of GGPP, which restores geranylgeranylation. Furthermore, the specific inhibition of geranylation using GGTI-298 has similar effects as zoledronic acid, whereas inhibition of farnesylation has no effects. This is in line with a number of previous studies, which have described most anti-tumor effects of bisphosphonates to be mediated by an inhibited geranylgeranylation rather than an inhibition of farnesylation [20]. In combination with the previously described anti-angiogenic effects of zoledronic acid [14], these anti-adhesive effects may negatively influence the metastatic potential of breast cancer cells. Of note, effects were greater in the highly osteotropic MDA-Bone cells, indicating a potential higher sensitivity in breast cancer cells with a higher metastatic risk.