irc-110160 and Breast-Neoplasms

Raf kinase inhibitor protein (RKIP) is a member of the phosphatidylethanolamine-binding-protein (PEBP) family that modulates the action of many kinases involved in cellular growth, apoptosis, epithelial to mesenchymal transition, motility, invasion and metastasis. Previously, we described an inverse association between RKIP and signal transducers and activators of transcription 3 (STAT3) expression in gastric adenocarcinoma patients. In this study, we elucidated the mechanism by which RKIP regulates STAT3 activity in breast and prostate cancer cell lines. RKIP over expression inhibited c-Src auto-phosphorylation and activation, as well as IL-6-, JAK1 and 2-, and activated Raf-mediated STAT3 tyrosine and serine phosphorylation and subsequent activation. In MDA-231 breast cancer cells that stably over express RKIP, IL-6 treatment blocked STAT3 phosphorylation and transcriptional activation. Conversely, in RKIP knockdown MDA-231 cells: STAT3 phosphorylation and activation increased in comparison to parental MDA-231 cells. RKIP over expression resulted in constitutive physical interaction with STAT3 and blocked c-Src and STAT3 association. The treatment of DU145 prostate, but not PC3 prostate or MDA-231 breast, cancer cell lines with ENMD-1198 or MKC-1 dramatically increased expression of RKIP. Overexpression of RKIP sensitized PC3 and MDA-231 cells to MTI-induced apoptosis. Moreover, MTI treatment resulted in a decrease in Src-mediated STAT3 tyrosine phosphorylation and activation, an effect that was significantly enhanced by RKIP over expression. In stable RKIP over expressing MDA-231 cells, tumor xenograft growth induced by activated STAT3 is inhibited. RKIP synergizes with MTIs to induce apoptosis and inhibit STAT3 activation of breast and prostate cancer cells. RKIP plays a critical role in opposing the effects of pro-oncogenic STAT3 activation.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estrenes; Female; Humans; Interleukin-6; Janus Kinase 1; Male; Mice; Neoplasm Transplantation; Phosphatidylethanolamine Binding Protein; Prostatic Neoplasms; STAT3 Transcription Factor; Transfection; Tubulin Modulators

It has been estimated that 70% of advanced breast cancer patients will face the complication of bone metastases. Three processes are pivotal during bone metastatic growth of breast cancer, namely, tumor cell proliferation, angiogenesis, and osteolysis. During tumor-induced osteolysis, a number of cytokines and growth factors are released from the degraded bone matrix. These factors stimulate further tumor growth, tumor angiogenesis, and tumor-induced osteolysis. New therapies should target all relevant processes to halt this powerful feedback loop. Here, we characterized the new 2-methoxyestradiol analogue ENMD-1198 and showed that it is cytotoxic to tumor cells. Moreover, ENMD-1198 showed both antiangiogenic and vascular disruptive properties and was capable of protecting the bone against tumor-induced osteolysis. We confirmed the in vitro data with a series of in vivo experiments showing the beneficial effects of ENMD-1198 and ENMD-1198-based combination treatments of metastatic breast cancer in bone both on tumor progression and on survival with long-term ENMD-1198 treatment. We confirmed the in vivo relevance of the ENMD-1198 protective effect on bone both with X-ray radiographs and microcomputed tomography. In addition, we combined ENMD-1198 treatment with low-dose metronomic cyclophosphamide and the bisphosphonate risedronic acid, leading to a mild increase in treatment efficacy.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Bone Resorption; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Survival; Estrenes; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Osteoclasts; Osteolysis; Pregnancy; Tumor Burden