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  • Bisphosphonates significantly reduce or prevent SREs The use

    2019-05-16

    Bisphosphonates significantly reduce or prevent SREs. The use of Zol for patients with bone metastases is currently the gold standard treatment [4]. However, it is still unclear whether Zol contributes to a survival benefit [9]. Niikura et al. recently reported that Zol did not prolong progression-free survival or overall survival of breast cancer patients with bone-only metastasis [10]. We aimed to enhance the anti-tumor effects on bone metastasis, epidermal growth factor receptor (EGFR)-tyrosin kinase inhibitor, gefitinib was used with Zol treatment. Epidermal growth factor (EGF) signaling is also an important mediator of bone metastasis. The EGFR is overexpressed in a wide variety of cancer types including ∼30% of breast cancers [11]. In addition to direct stimulation to cancer cell proliferation, EGF signaling has been implicated in the modulation of stromal gap-26 in the tumor microenvironment [12,13]. Bone metastasis of the breast cancer clonal cell line MDA-MB-231, which overexpresses EGFR but lacks a proliferative response to EGF, is markedly suppressed by inhibition of EGFR-tyrosine kinase. In fact, significant relief of bone pain in breast cancer patients with bone metastases has been observed in a clinical trial of the EGFR-tyrosine kinase inhibitor gefitinib [14,15]. We have studied a bone-seeking clonal cell line that was established by repeated sequential passages of metastatic cells from bone in nude mice and also in vitro, and shown that it metastasizes exclusively to bone, producing larger osteolytic lesions than the MDA-MB-231 parental cells. In contrast, MDA-MB-231 cells target other organs such as brain, ovary, liver, and adrenal gland. The biological properties of this bone-seeking clone were shown to differ from those of MDA-MB-231, the former producing more parathyroid hormone-released protein than the latter. Activation of insulin-like growth factor I occurred, and anchorage-independent growth was not inhibited by transforming growth factor β[16].
    Materials and methods
    Results
    Discussion Zol acts against osteolytic bone metastasis by inducing isoprenylation of proteins that are required for osteoclast survival. It also induces apoptosis in several types of cancers, including primary breast cancer, through the pathway responsible for prenylation of small GTP-binding proteins [18]. It is well known that EGF is an anti-apoptotic factor, and it is conceivable that gefitinib might enhance the susceptibility of cancer cells to apoptosis. In fact, a combination of Zol and gefitinib with SC-234 was reported to elicit a cooperative anti-tumor effect in a non-bone metastatic model of breast and prostate cancer [19]. Such combined treatment has also been reported to elicit a tumor-suppressive effect, which is significantly more effective and less toxic in vitro and in vivo, on EGFR-mutated non-small cell lung carcinoma cells, in comparison with the individual anti-tumor effect of gefitinib or Zol alone [20]. In the present study using a bone-seeking breast cancer clonal cell line in vitro, we demonstrated an enhanced inhibitory effect on bone metastasis using Zol plus gefitinib in combination. The bone-seeking clone used in this study showed higher expression of stathmin than the parental MDA-MB-231 cell line. Similarly, using 2-D DIGE and mass spectrometry, Xu et al. have demonstrated that stathmin-1 was up-regulated in a highly metastatic variant of MDA-MB-231 [21]. A proteomic analysis designed to examine the time course of neoplastic transformation of human mammary epithelial cells showed that stathmin was up-regulated in parallel with an early and progressive increase in metastatic potential [22]. Moreover, overexpression of stathmin has been detected in different types of human malignant tissue, such as sarcoma [23], gastric cancer [24], endometrial cancer [25], colon cancer [26], nasopharyngeal cancer [27], and breast cancer [28,29]. All these data suggest that overexpression of stathmin is significantly correlated with clinically aggressive behavior such as lymph node metastasis, poor histologic differentiation, an advanced clinical stage, or poor prognosis.