{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T15:34:03Z","timestamp":1785598443142,"version":"3.56.0"},"reference-count":188,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T00:00:00Z","timestamp":1620691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Solid tumors, such as breast cancer and prostate cancer, often form bone metastases in the course of the disease. Patients with bone metastases frequently develop complications, such as pathological fractures or hypercalcemia and exhibit a reduced life expectancy. Thus, it is of vital importance to improve the treatment of bone metastases. A possible approach is to target signaling pathways, such as the PI3K\/AKT pathway, which is frequently dysregulated in solid tumors. Therefore, we sought to review the role of the serine\/threonine kinase AKT in bone metastasis. In general, activation of AKT signaling was shown to be associated with the formation of bone metastases from solid tumors. More precisely, AKT gets activated in tumor cells by a plethora of bone-derived growth factors and cytokines. Subsequently, AKT promotes the bone-metastatic capacities of tumor cells through distinct signaling pathways and secretion of bone cell-stimulating factors. Within the crosstalk between tumor and bone cells, also known as the vicious cycle, the stimulation of osteoblasts and osteoclasts also causes activation of AKT in these cells. As a consequence, bone metastasis is reduced after experimental inhibition of AKT. In summary, AKT signaling could be a promising therapeutical approach for patients with bone metastases of solid tumors.<\/jats:p>","DOI":"10.3390\/cancers13102287","type":"journal-article","created":{"date-parts":[[2021,5,11]],"date-time":"2021-05-11T04:05:32Z","timestamp":1620705932000},"page":"2287","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["AKT in Bone Metastasis of Solid Tumors: A Comprehensive Review"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6069-9787","authenticated-orcid":false,"given":"Nico","family":"Hinz","sequence":"first","affiliation":[{"name":"Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2176-6526","authenticated-orcid":false,"given":"Manfred","family":"J\u00fccker","sequence":"additional","affiliation":[{"name":"Center for Experimental Medicine, Institute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1007\/s10585-015-9697-2","article-title":"Pattern of metastasis and outcome in patients with breast cancer","volume":"32","author":"Gerratana","year":"2015","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sternberg, C.N., Baskin-Bey, E.S., Watson, M., Worsfold, A., Rider, A., and Tombal, B. (2013). Treatment patterns and characteristics of European patients with castration-resistant prostate cancer. BMC Urol., 13.","DOI":"10.1186\/1471-2490-13-58"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1053\/ctrv.2000.0210","article-title":"Metastatic bone disease: Clinical features, pathophysiology and treatment strategies","volume":"27","author":"Coleman","year":"2001","journal-title":"Cancer Treat. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/nrc2622","article-title":"Metastasis: From dissemination to organ-specific colonization","volume":"9","author":"Nguyen","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.cell.2006.11.001","article-title":"Cancer metastasis: Building a framework","volume":"127","author":"Gupta","year":"2006","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s13046-017-0578-1","article-title":"Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trials","volume":"36","author":"Gdowski","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nrc.2016.44","article-title":"Bone metastasis: The importance of the neighbourhood","volume":"16","author":"Croucher","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8+<1546::AID-CNCR4>3.0.CO;2-I","article-title":"Mechanisms of bone metastasis","volume":"80","author":"Mundy","year":"1997","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nrc3055","article-title":"Cancer to bone: A fatal attraction","volume":"11","author":"Weilbaecher","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_10","first-page":"98","article-title":"The distribution of secondary growths in cancer of the breast","volume":"8","author":"Paget","year":"1889","journal-title":"Cancer Met. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1172\/JCI22320","article-title":"Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors","volume":"115","author":"Minn","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/nature03799","article-title":"Genes that mediate breast cancer metastasis to lung","volume":"436","author":"Minn","year":"2005","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/S1535-6108(03)00132-6","article-title":"A multigenic program mediating breast cancer metastasis to bone","volume":"3","author":"Kang","year":"2003","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1023\/A:1015599831232","article-title":"Prostate carcinoma skeletal metastases: Cross-talk between tumor and bone","volume":"20","author":"Keller","year":"2001","journal-title":"Cancer Metastasis Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nrc867","article-title":"Metastasis to bone: Causes, consequences and therapeutic opportunities","volume":"2","author":"Mundy","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Roato, I., D\u2019Amelio, P., Gorassini, E., Grimaldi, A., Bonello, L., Fiori, C., Delsedime, L., Tizzani, A., De Libero, A., and Isaia, G. (2008). Osteoclasts are active in bone forming metastases of prostate cancer patients. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003627"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1002\/1097-0142(20000615)88:12+<2989::AID-CNCR14>3.0.CO;2-Q","article-title":"The natural history, skeletal complications, and management of bone metastases in patients with prostate carcinoma","volume":"88","author":"Carlin","year":"2000","journal-title":"Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1056\/NEJMra030831","article-title":"Mechanisms of bone metastasis","volume":"350","author":"Roodman","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41413-020-00105-1","article-title":"Molecular mechanisms and clinical management of cancer bone metastasis","volume":"8","author":"Wang","year":"2020","journal-title":"Bone Res."},{"key":"ref_20","first-page":"570","article-title":"The vicious cycle of bone metastases","volume":"2","author":"Guise","year":"2002","journal-title":"J. Musculoskelet. Neuronal. Interact."},{"key":"ref_21","first-page":"308","article-title":"Tumor-bone cellular interactions in skeletal metastases","volume":"4","author":"Chirgwin","year":"2004","journal-title":"J. Musculoskelet. Neuronal. Interact."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"24571","DOI":"10.1074\/jbc.M202561200","article-title":"Transforming growth factor-beta stimulates parathyroid hormone-related protein and osteolytic metastases via Smad and mitogen-activated protein kinase signaling pathways","volume":"277","author":"Kakonen","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4451","DOI":"10.1210\/endo.140.10.7037","article-title":"Breast cancer cells interact with osteoblasts to support osteoclast formation","volume":"140","author":"Thomas","year":"1999","journal-title":"Endocrinology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1002\/cncr.22991","article-title":"Pathologic fractures correlate with reduced survival in patients with malignant bone disease","volume":"110","author":"Saad","year":"2007","journal-title":"Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/358157a0","article-title":"Platelet-derived growth factor stimulates synthesis of PtdIns(3,4,5)P3 by activating a PtdIns(4,5)P2 3-OH kinase","volume":"358","author":"Hawkins","year":"1992","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6541","DOI":"10.1002\/j.1460-2075.1996.tb01045.x","article-title":"Mechanism of activation of protein kinase B by insulin and IGF-1","volume":"15","author":"Alessi","year":"1996","journal-title":"EMBO J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1042\/bj20031229","article-title":"Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change","volume":"375","author":"Milburn","year":"2003","journal-title":"Biochem. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/S0960-9822(06)00122-9","article-title":"Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha","volume":"7","author":"Alessi","year":"1997","journal-title":"Curr. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.molcel.2008.02.024","article-title":"PKBalpha\/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival","volume":"30","author":"Bozulic","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0092-8674(00)81780-8","article-title":"Negative regulation of PKB\/Akt-dependent cell survival by the tumor suppressor PTEN","volume":"95","author":"Stambolic","year":"1998","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0079-6107(98)00049-2","article-title":"The role of SHIP in growth factor induced signalling","volume":"71","author":"Huber","year":"1999","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31515","DOI":"10.1074\/jbc.272.50.31515","article-title":"Role of translocation in the activation and function of protein kinase B","volume":"272","author":"Andjelkovic","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.cell.2007.06.009","article-title":"AKT\/PKB signaling: Navigating downstream","volume":"129","author":"Manning","year":"2007","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.bcp.2014.05.011","article-title":"Targeting PI3K\/AKT\/mTOR pathway in non small cell lung cancer","volume":"90","author":"Fumarola","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Cao, J., Zhu, S., Zhou, W., Li, J., Liu, C., Xuan, H., Yan, J., Zheng, L., Zhou, L., and Yu, J. (2013). PLZF mediates the PTEN\/AKT\/FOXO3a signaling in suppression of prostate tumorigenesis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0077922"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"24500","DOI":"10.1074\/jbc.M003145200","article-title":"Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression","volume":"275","author":"Graff","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5232","DOI":"10.1158\/0008-5472.CAN-04-0272","article-title":"Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer","volume":"64","author":"Kreisberg","year":"2004","journal-title":"Cancer Res."},{"key":"ref_38","first-page":"164","article-title":"Progress in targeted therapy for breast cancer","volume":"4","author":"Ju","year":"2018","journal-title":"Chronic Dis. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1111\/1759-7714.13328","article-title":"Targeting the PI3K\/Akt\/mTOR pathway in non-small cell lung cancer (NSCLC)","volume":"11","author":"Tan","year":"2020","journal-title":"Thorac. Cancer"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.18632\/oncotarget.1314","article-title":"Combinatorial antitumor effect of HDAC and the PI3K-Akt-mTOR pathway inhibition in a Pten defecient model of prostate cancer","volume":"4","author":"Ellis","year":"2013","journal-title":"Oncotarget"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Kawamura, N., Kugimiya, F., Oshima, Y., Ohba, S., Ikeda, T., Saito, T., Shinoda, Y., Kawasaki, Y., Ogata, N., and Hoshi, K. (2007). Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0001058"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3583","DOI":"10.1074\/jbc.M410480200","article-title":"Akt1\/Akt2 and mammalian target of rapamycin\/Bim play critical roles in osteoclast differentiation and survival, respectively, whereas Akt is dispensable for cell survival in isolated osteoclast precursors","volume":"280","author":"Sugatani","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S8756-3282(01)00657-3","article-title":"The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation","volume":"30","author":"Lee","year":"2002","journal-title":"Bone"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"163","DOI":"10.4049\/jimmunol.1101254","article-title":"Akt induces osteoclast differentiation through regulating the GSK3beta\/NFATc1 signaling cascade","volume":"188","author":"Moon","year":"2012","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Suzuki, E., Ochiai-Shino, H., Aoki, H., Onodera, S., Saito, A., Saito, A., and Azuma, T. (2014). Akt activation is required for TGF-beta1-induced osteoblast differentiation of MC3T3-E1 pre-osteoblasts. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112566"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.clbc.2012.11.001","article-title":"Incidence and patterns of distant metastases for patients with early-stage breast cancer after breast conservation treatment","volume":"13","author":"Berman","year":"2013","journal-title":"Clin. Breast Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"287","DOI":"10.2147\/CMAR.S155524","article-title":"Bone metastasis pattern in initial metastatic breast cancer: A population-based study","volume":"10","author":"Xiong","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5649","DOI":"10.1038\/s41388-020-01391-z","article-title":"Targeting disseminated estrogen-receptor-positive breast cancer cells in bone marrow","volume":"39","author":"Buschhaus","year":"2020","journal-title":"Oncogene"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1158\/0008-5472.CAN-18-0056","article-title":"Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells","volume":"78","author":"Liu","year":"2018","journal-title":"Cancer Res."},{"key":"ref_50","first-page":"361","article-title":"S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer","volume":"6","author":"Khotskaya","year":"2014","journal-title":"Am. J. Transl. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e12032","DOI":"10.1097\/MD.0000000000012032","article-title":"Exploring the molecular mechanism associated with breast cancer bone metastasis using bioinformatic analysis and microarray genetic interaction network","volume":"97","author":"Chen","year":"2018","journal-title":"Medicine"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3640","DOI":"10.7150\/jca.26825","article-title":"Somatic mutations, clinicopathologic characteristics, and survival in patients with untreated breast cancer with bone-only and non-bone sites of first metastasis","volume":"9","author":"Kono","year":"2018","journal-title":"J. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"323","DOI":"10.2147\/OTT.S226770","article-title":"Transcriptome Analysis Reveals Key Genes and Pathways Associated with Metastasis in Breast Cancer","volume":"13","author":"Li","year":"2020","journal-title":"OncoTargets Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ccell.2014.11.017","article-title":"The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells","volume":"27","author":"Wang","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1158\/2159-8290.CD-14-1042","article-title":"Suppression of early hematogenous dissemination of human breast cancer cells to bone marrow by retinoic Acid-induced 2","volume":"5","author":"Werner","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1186\/s12935-019-0986-8","article-title":"Overexpression of CENPF correlates with poor prognosis and tumor bone metastasis in breast cancer","volume":"19","author":"Sun","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3822","DOI":"10.1016\/j.yexcr.2006.08.011","article-title":"PTH-related protein upregulates integrin alpha6beta4 expression and activates Akt in breast cancer cells","volume":"312","author":"Shen","year":"2006","journal-title":"Exp. Cell Res."},{"key":"ref_58","first-page":"1477","article-title":"Potential role of HER-2 in primary breast tumor with bone metastasis","volume":"15","author":"Kim","year":"2006","journal-title":"Oncol. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3892\/ol.2014.2096","article-title":"Chemokine (C-X-C motif) receptor 4 RNA interference inhibits bone metastasis in breast cancer","volume":"8","author":"Zeng","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s10555-006-9019-x","article-title":"The pivotal role of CXCL12 (SDF-1)\/CXCR4 axis in bone metastasis","volume":"25","author":"Wang","year":"2006","journal-title":"Cancer Metastasis Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6493","DOI":"10.1158\/0008-5472.CAN-04-1303","article-title":"CXCL-12\/stromal cell-derived factor-1alpha transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation","volume":"65","author":"Cabioglu","year":"2005","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/jcmm.12004","article-title":"Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells","volume":"17","author":"Mimeault","year":"2013","journal-title":"J. Cell. Mol. Med."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.ccr.2009.05.017","article-title":"Latent bone metastasis in breast cancer tied to Src-dependent survival signals","volume":"16","author":"Zhang","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2013.07.036","article-title":"Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma","volume":"154","author":"Zhang","year":"2013","journal-title":"Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"9502","DOI":"10.18632\/oncotarget.3321","article-title":"TRAIL-R2 promotes skeletal metastasis in a breast cancer xenograft mouse model","volume":"6","author":"Fritsche","year":"2015","journal-title":"Oncotarget"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Futakuchi, M., Lami, K., Tachibana, Y., Yamamoto, Y., Furukawa, M., and Fukuoka, J. (2019). The Effects of TGF-beta Signaling on Cancer Cells and Cancer Stem Cells in the Bone Microenvironment. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205117"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1002\/mc.20411","article-title":"Osteoblasts-derived TGF-beta1 enhance motility and integrin upregulation through Akt, ERK, and NF-kappaB-dependent pathway in human breast cancer cells","volume":"47","author":"Wei","year":"2008","journal-title":"Mol. Carcinog."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"15021","DOI":"10.1038\/ncomms15021","article-title":"FAF1 phosphorylation by AKT accumulates TGF-beta type II receptor and drives breast cancer metastasis","volume":"8","author":"Xie","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"179","DOI":"10.11005\/jbm.2019.26.3.179","article-title":"Mechanical and Mechanosensing Properties of Tumor Affected Bone Cells Were Inhibited via PI3K\/Akt Pathway","volume":"26","author":"Lee","year":"2019","journal-title":"J. Bone Metab."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"4238","DOI":"10.1158\/0008-5472.CAN-11-3061","article-title":"Bone-derived IGF mediates crosstalk between bone and breast cancer cells in bony metastases","volume":"72","author":"Hiraga","year":"2012","journal-title":"Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"336","DOI":"10.21037\/atm.2020.02.110","article-title":"AZD3463, an IGF-1R inhibitor, suppresses breast cancer metastasis to bone via modulation of the PI3K-Akt pathway","volume":"8","author":"Hu","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1002\/jbmr.1847","article-title":"Selective tyrosine kinase inhibition of insulin-like growth factor-1 receptor inhibits human and mouse breast cancer-induced bone cell activity, bone remodeling, and osteolysis","volume":"28","author":"Logan","year":"2013","journal-title":"J. Bone Miner. Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"4730","DOI":"10.1038\/onc.2015.518","article-title":"Role of Runx2 in IGF-1Rbeta\/Akt- and AMPK\/Erk-dependent growth, survival and sensitivity towards metformin in breast cancer bone metastasis","volume":"35","author":"Tandon","year":"2016","journal-title":"Oncogene"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1186\/s12943-015-0404-3","article-title":"RUNX2 and the PI3K\/AKT axis reciprocal activation as a driving force for tumor progression","volume":"14","author":"Boregowda","year":"2015","journal-title":"Mol. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3109\/08977194.2014.894037","article-title":"Bone-derived soluble factors and laminin-511 cooperate to promote migration, invasion and survival of bone-metastatic breast tumor cells","volume":"32","author":"Denoyer","year":"2014","journal-title":"Growth Factors"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1177\/1947601911400901","article-title":"c-Jun N-terminal Kinase 2 Regulates Multiple Receptor Tyrosine Kinase Pathways in Mouse Mammary Tumor Growth and Metastasis","volume":"2","author":"Nasrazadani","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Katagiri, T., and Watabe, T. (2016). Bone Morphogenetic Proteins. Cold Spring Harb. Perspect. Biol., 8.","DOI":"10.1101\/cshperspect.a021899"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Ren, W., Liu, Y., Wan, S., Fei, C., Wang, W., Chen, Y., Zhang, Z., Wang, T., Wang, J., and Zhou, L. (2014). BMP9 inhibits proliferation and metastasis of HER2-positive SK-BR-3 breast cancer cells through ERK1\/2 and PI3K\/AKT pathways. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096816"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s13402-014-0197-1","article-title":"BMP9 regulates cross-talk between breast cancer cells and bone marrow-derived mesenchymal stem cells","volume":"37","author":"Wan","year":"2014","journal-title":"Cell Oncol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"17039","DOI":"10.1038\/cddiscovery.2017.39","article-title":"BMP-2 induces EMT and breast cancer stemness through Rb and CD44","volume":"3","author":"Huang","year":"2017","journal-title":"Cell Death Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"22049","DOI":"10.1074\/jbc.M115.649608","article-title":"Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis","volume":"290","author":"Sophocleous","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3175","DOI":"10.1158\/0008-5472.CAN-12-0481","article-title":"CXCL10 promotes osteolytic bone metastasis by enhancing cancer outgrowth and osteoclastogenesis","volume":"72","author":"Lee","year":"2012","journal-title":"Cancer Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"812","DOI":"10.3892\/ijo.2016.3538","article-title":"Increased regucalcin gene expression extends survival in breast cancer patients: Overexpression of regucalcin suppresses the proliferation and metastatic bone activity in MDA-MB-231 human breast cancer cells in vitro","volume":"49","author":"Yamaguchi","year":"2016","journal-title":"Int. J. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13058-020-01301-x","article-title":"Enhanced mitochondrial fission suppresses signaling and metastasis in triple-negative breast cancer","volume":"22","author":"Humphries","year":"2020","journal-title":"Breast Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Du, W.W., Fang, L., Yang, W., Sheng, W., Zhang, Y., Seth, A., Yang, B.B., and Yee, A.J. (2012). The role of versican G3 domain in regulating breast cancer cell motility including effects on osteoblast cell growth and differentiation in vitro\u2014Evaluation towards understanding breast cancer cell bone metastasis. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-341"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1677\/erc.1.00956","article-title":"Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: Implications for the pathogenesis and treatment of bone metastasis","volume":"12","author":"Normanno","year":"2005","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.cyto.2018.03.032","article-title":"M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mTORC2 and promotes tumor growth and metastasis","volume":"118","author":"Shrivastava","year":"2019","journal-title":"Cytokine"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.canlet.2018.11.038","article-title":"Phosphatidyl inositol 3-kinase (PI3K)-mTOR inhibitor PKI-402 inhibits breast cancer induced osteolysis","volume":"443","author":"Yuan","year":"2019","journal-title":"Cancer Lett."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/s41419-018-0417-0","article-title":"Raddeanin A suppresses breast cancer-associated osteolysis through inhibiting osteoclasts and breast cancer cells","volume":"9","author":"Wang","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"19074","DOI":"10.1038\/srep19074","article-title":"Dihydroartemisinin prevents breast cancer-induced osteolysis via inhibiting both breast caner cells and osteoclasts","volume":"6","author":"Feng","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"8173","DOI":"10.1002\/cam4.3432","article-title":"Asperolide A prevents bone metastatic breast cancer via the PI3K\/AKT\/mTOR\/c-Fos\/NFATc1 signaling pathway","volume":"9","author":"Jiang","year":"2020","journal-title":"Cancer Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"555","DOI":"10.3892\/ijo.2014.2769","article-title":"Wedelolactone inhibits breast cancer-induced osteoclastogenesis by decreasing Akt\/mTOR signaling","volume":"46","author":"Hsieh","year":"2015","journal-title":"Int. J. Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1002\/ijc.26014","article-title":"Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo","volume":"130","author":"Urakawa","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1093\/annonc\/mdr159","article-title":"Zoledronic acid blocks the interaction between mesenchymal stem cells and breast cancer cells: Implications for adjuvant therapy of breast cancer","volume":"23","author":"Gallo","year":"2012","journal-title":"Ann. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.ejca.2010.02.026","article-title":"Interleukin-6 in bone metastasis and cancer progression","volume":"46","author":"Ara","year":"2010","journal-title":"Eur. J. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1158\/1535-7163.MCT-10-0836","article-title":"CCN1, a candidate target for zoledronic acid treatment in breast cancer","volume":"10","author":"Espinoza","year":"2011","journal-title":"Mol. Cancer Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1002\/ijc.24710","article-title":"Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha\/VEGF signaling pathways in human breast cancer cells","volume":"126","author":"Tang","year":"2010","journal-title":"Int. J. Cancer"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"29321","DOI":"10.18632\/oncotarget.8722","article-title":"Can the microRNA expression profile help to identify novel targets for zoledronic acid in breast cancer?","volume":"7","author":"Fanale","year":"2016","journal-title":"Oncotarget"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s00210-016-1224-8","article-title":"The miR-21\/PTEN\/Akt signaling pathway is involved in the anti-tumoral effects of zoledronic acid in human breast cancer cell lines","volume":"389","author":"Fragni","year":"2016","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1010428318771773","DOI":"10.1177\/1010428318771773","article-title":"Dual PI3 K\/mTOR inhibition reduces prostate cancer bone engraftment altering tumor-induced bone remodeling","volume":"40","author":"Mancini","year":"2018","journal-title":"Tumour. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Lescarbeau, R.M., Seib, F.P., Prewitz, M., Werner, C., and Kaplan, D.L. (2012). In vitro model of metastasis to bone marrow mediates prostate cancer castration resistant growth through paracrine and extracellular matrix factors. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0040372"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"9206","DOI":"10.18632\/oncotarget.24104","article-title":"Tumor microenvironment promotes prostate cancer cell dissemination via the Akt\/mTOR pathway","volume":"9","author":"Shi","year":"2018","journal-title":"Oncotarget"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Mimeault, M., Johansson, S.L., and Batra, S.K. (2012). Pathobiological implications of the expression of EGFR, pAkt, NF-kappaB and MIC-1 in prostate cancer stem cells and their progenies. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031919"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1186\/s40425-019-0753-3","article-title":"Distinct tumor microenvironments of lytic and blastic bone metastases in prostate cancer patients","volume":"7","author":"Ihle","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/jcmm.12010","article-title":"Bone marrow mesenchymal stem cells increase motility of prostate cancer cells via production of stromal cell-derived factor-1alpha","volume":"17","author":"Mognetti","year":"2013","journal-title":"J. Cell. Mol. Med."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1476-4598-12-85","article-title":"PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12\/CXCR4 signaling","volume":"12","author":"Saliganan","year":"2013","journal-title":"Mol. Cancer"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/pros.20318","article-title":"CXCL12\/CXCR4 signaling activates Akt-1 and MMP-9 expression in prostate cancer cells: The role of bone microenvironment-associated CXCL12","volume":"66","author":"Chinni","year":"2006","journal-title":"Prostate"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1093\/carcin\/bgr065","article-title":"Olfactomedin 4 suppresses prostate cancer cell growth and metastasis via negative interaction with cathepsin D and SDF-1","volume":"32","author":"Chen","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1093\/jnci\/djq044","article-title":"Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth","volume":"102","author":"Zhang","year":"2010","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1002\/pros.20870","article-title":"PI3K\/Akt-dependent transcriptional regulation and activation of BMP-2-Smad signaling by NF-kappaB in metastatic prostate cancer cells","volume":"69","author":"Graham","year":"2009","journal-title":"Prostate"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1002\/pros.20799","article-title":"Osteoblasts-derived BMP-2 enhances the motility of prostate cancer cells via activation of integrins","volume":"68","author":"Lai","year":"2008","journal-title":"Prostate"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1093\/carcin\/bgt103","article-title":"CCN3 promotes prostate cancer bone metastasis by modulating the tumor-bone microenvironment through RANKL-dependent pathway","volume":"34","author":"Chen","year":"2013","journal-title":"Carcinogenesis"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1093\/carcin\/bgs108","article-title":"CCN3 increases cell motility and ICAM-1 expression in prostate cancer cells","volume":"33","author":"Chen","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/sj.neo.7900224","article-title":"The role of alpha(v)beta(3) in prostate cancer progression","volume":"4","author":"Cooper","year":"2002","journal-title":"Neoplasia"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"4571","DOI":"10.1158\/0008-5472.CAN-13-0218","article-title":"Vitronectin-alphavbeta3 integrin engagement directs hypoxia-resistant mTOR activity and sustained protein synthesis linked to invasion by breast cancer cells","volume":"73","author":"Pola","year":"2013","journal-title":"Cancer Res."},{"key":"ref_116","first-page":"726","article-title":"SB225002 inhibits prostate cancer invasion and attenuates the expression of BSP, OPN and MMP2","volume":"40","author":"Xu","year":"2018","journal-title":"Oncol. Rep."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"3257","DOI":"10.1158\/0008-5472.CAN-10-2603","article-title":"FOXO1 inhibits Runx2 transcriptional activity and prostate cancer cell migration and invasion","volume":"71","author":"Zhang","year":"2011","journal-title":"Cancer Res."},{"key":"ref_118","first-page":"4702","article-title":"Prostaglandin E2 receptor EP4 is involved in the cell growth and invasion of prostate cancer via the cAMPPKA\/PI3KAkt signaling pathway","volume":"17","author":"Xu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"e2572","DOI":"10.1038\/cddis.2017.15","article-title":"MicroRNA-466 inhibits tumor growth and bone metastasis in prostate cancer by direct regulation of osteogenic transcription factor RUNX2","volume":"8","author":"Colden","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"4636","DOI":"10.1158\/1078-0432.CCR-14-0305","article-title":"miR-409-3p\/-5p promotes tumorigenesis, epithelial-to-mesenchymal transition, and bone metastasis of human prostate cancer","volume":"20","author":"Josson","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1038\/bjc.2012.457","article-title":"Ligand-independent activation of EphA2 by arachidonic acid induces metastasis-like behaviour in prostate cancer cells","volume":"107","author":"Tawadros","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"100955","DOI":"10.1016\/j.tranon.2020.100955","article-title":"Progression-free survival of prostate cancer patients is prolonged with a higher regucalcin expression in the tumor tissues: Overexpressed regucalcin suppresses the growth and bone activity in human prostate cancer cells","volume":"14","author":"Yamaguchi","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1038\/onc.2014.116","article-title":"Talin1 phosphorylation activates beta1 integrins: A novel mechanism to promote prostate cancer bone metastasis","volume":"34","author":"Jin","year":"2015","journal-title":"Oncogene"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1002\/ijc.28948","article-title":"Bone-induced c-kit expression in prostate cancer: A driver of intraosseous tumor growth","volume":"136","author":"Mainetti","year":"2015","journal-title":"Int. J. Cancer"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1158\/0008-5472.CAN-06-2593","article-title":"Human bone marrow activates the Akt pathway in metastatic prostate cells through transactivation of the alpha-platelet-derived growth factor receptor","volume":"67","author":"Dolloff","year":"2007","journal-title":"Cancer Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"6848","DOI":"10.1038\/sj.onc.1208815","article-title":"Bone-metastatic potential of human prostate cancer cells correlates with Akt\/PKB activation by alpha platelet-derived growth factor receptor","volume":"24","author":"Dolloff","year":"2005","journal-title":"Oncogene"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1186\/1476-4598-13-208","article-title":"Induction of integrin alpha2 in a highly bone metastatic human prostate cancer cell line: Roles of RANKL and AR under three-dimensional suspension culture","volume":"13","author":"Ziaee","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1002\/pros.20903","article-title":"EGFR ligand switch in late stage prostate cancer contributes to changes in cell signaling and bone remodeling","volume":"69","author":"DeHaan","year":"2009","journal-title":"Prostate"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"6917","DOI":"10.1038\/s41598-019-43294-4","article-title":"Interleukin-7 Contributes to the Invasiveness of Prostate Cancer Cells by Promoting Epithelial-Mesenchymal Transition","volume":"9","author":"Seol","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"9065","DOI":"10.1158\/0008-5472.CAN-06-0317","article-title":"Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis","volume":"66","author":"Liao","year":"2006","journal-title":"Cancer Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s13046-018-0813-4","article-title":"Downregulation of miR-133a-3p promotes prostate cancer bone metastasis via activating PI3K\/AKT signaling","volume":"37","author":"Tang","year":"2018","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"6213s","DOI":"10.1158\/1078-0432.CCR-06-1007","article-title":"Basic mechanisms responsible for osteolytic and osteoblastic bone metastases","volume":"12","author":"Guise","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s12013-014-0433-3","article-title":"Effect of PI3K\/Akt Signaling Pathway on the Process of Prostate Cancer Metastasis to Bone","volume":"72","author":"Zhu","year":"2015","journal-title":"Cell Biochem. Biophys."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1158\/1535-7163.MCT-17-1002","article-title":"Recombinant MDA-7\/IL24 Suppresses Prostate Cancer Bone Metastasis through Downregulation of the Akt\/Mcl-1 Pathway","volume":"17","author":"Pradhan","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1002\/ctm2.27","article-title":"Prostate-specific antigen modulates the osteogenic differentiation of MSCs via the cadherin 11-Akt axis","volume":"10","author":"Wu","year":"2020","journal-title":"Clin. Transl. Med."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"321","DOI":"10.2174\/1568009618666180911101310","article-title":"In Vitro and In Vivo Antimetastatic Effects of ZSTK474 on Prostate Cancer DU145 Cells","volume":"19","author":"Liu","year":"2019","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"20891","DOI":"10.1074\/jbc.M116.727875","article-title":"The MET\/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer","volume":"291","author":"Watanabe","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1159\/000430350","article-title":"Pristimerin Inhibits Prostate Cancer Bone Metastasis by Targeting PC-3 Stem Cell Characteristics and VEGF-Induced Vasculogenesis of BM-EPCs","volume":"37","author":"Huang","year":"2015","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_139","doi-asserted-by":"crossref","unstructured":"Hsu, Y.H., Wu, C.Y., Hsing, C.H., Lai, W.T., Wu, L.W., and Chang, M.S. (2015). Anti-IL-20 Monoclonal Antibody Suppresses Prostate Cancer Growth and Bone Osteolysis in Murine Models. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0139871"},{"key":"ref_140","doi-asserted-by":"crossref","unstructured":"Li, Y., Kong, D., Ahmad, A., Bao, B., and Sarkar, F.H. (2012). Targeting bone remodeling by isoflavone and 3,3\u2032-diindolylmethane in the context of prostate cancer bone metastasis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0033011"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"15541","DOI":"10.1073\/pnas.0805354105","article-title":"Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone","volume":"105","author":"Yano","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1158\/1078-0432.CCR-10-3077","article-title":"A novel HSP90 inhibitor delays castrate-resistant prostate cancer without altering serum PSA levels and inhibits osteoclastogenesis","volume":"17","author":"Lamoureux","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Dayyani, F., Parikh, N.U., Varkaris, A.S., Song, J.H., Moorthy, S., Chatterji, T., Maity, S.N., Wolfe, A.R., Carboni, J.M., and Gottardis, M.M. (2012). Combined Inhibition of IGF-1R\/IR and Src family kinases enhances antitumor effects in prostate cancer by decreasing activated survival pathways. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0051189"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1158\/1535-7163.MCT-09-0962","article-title":"SKI-606 (Bosutinib) blocks prostate cancer invasion, growth, and metastasis in vitro and in vivo through regulation of genes involved in cancer growth and skeletal metastasis","volume":"9","author":"Rabbani","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1593\/neo.10296","article-title":"An anti-urokinase plasminogen activator receptor antibody (ATN-658) blocks prostate cancer invasion, migration, growth, and experimental skeletal metastasis in vitro and in vivo","volume":"12","author":"Rabbani","year":"2010","journal-title":"Neoplasia"},{"key":"ref_146","doi-asserted-by":"crossref","unstructured":"Yates, T.J., Lopez, L.E., Lokeshwar, S.D., Ortiz, N., Kallifatidis, G., Jordan, A., Hoye, K., Altman, N., and Lokeshwar, V.B. (2015). Dietary supplement 4-methylumbelliferone: An effective chemopreventive and therapeutic agent for prostate cancer. J. Natl. Cancer Inst., 107.","DOI":"10.1093\/jnci\/djv085"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1158\/1535-7163.MCT-19-0387","article-title":"A Novel Salicylanilide Derivative Induces Autophagy Cell Death in Castration-Resistant Prostate Cancer via ER Stress-Activated PERK Signaling Pathway","volume":"19","author":"Hsieh","year":"2020","journal-title":"Mol. Cancer Ther."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"3818","DOI":"10.1158\/0008-5472.CAN-06-3879","article-title":"In vitro and in vivo molecular evidence for better therapeutic efficacy of ABT-627 and taxotere combination in prostate cancer","volume":"67","author":"Banerjee","year":"2007","journal-title":"Cancer Res."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1002\/(SICI)1097-0142(19971015)80:8+<1588::AID-CNCR9>3.0.CO;2-G","article-title":"Skeletal complications of malignancy","volume":"80","author":"Coleman","year":"1997","journal-title":"Cancer"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1097\/JTO.0b013e31819518fc","article-title":"Prevention and management of bone metastases in lung cancer: A review","volume":"4","author":"Clemons","year":"2009","journal-title":"J. Thorac. Oncol."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.lungcan.2008.09.003","article-title":"Osteopontin increases lung cancer cells migration via activation of the alphavbeta3 integrin\/FAK\/Akt and NF-kappaB-dependent pathway","volume":"64","author":"Fong","year":"2009","journal-title":"Lung Cancer"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"300060520939718","DOI":"10.1177\/0300060520939718","article-title":"Serum microRNA-365 suppresses non-small-cell lung cancer metastasis and invasion in patients with bone metastasis of lung cancer","volume":"48","author":"Liu","year":"2020","journal-title":"J. Int. Med. Res."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s10585-006-9006-1","article-title":"RANKL-induced CCL22\/macrophage-derived chemokine produced from osteoclasts potentially promotes the bone metastasis of lung cancer expressing its receptor CCR4","volume":"23","author":"Nakamura","year":"2006","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1302\/2046-3758.91.BJR-2019-0085.R2","article-title":"Effect of GNAQ alteration on RANKL-induced osteoclastogenesis in human non-small-cell lung cancer","volume":"9","author":"Choi","year":"2020","journal-title":"Bone Jt. Res."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"617","DOI":"10.3892\/or.2015.4028","article-title":"Syringetin suppresses osteoclastogenesis mediated by osteoblasts in human lung adenocarcinoma","volume":"34","author":"Tsai","year":"2015","journal-title":"Oncol. Rep."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1093\/carcin\/bgq030","article-title":"Phospholipase D signaling pathway is involved in lung cancer-derived IL-8 increased osteoclastogenesis","volume":"31","author":"Hsu","year":"2010","journal-title":"Carcinogenesis"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"150","DOI":"10.5483\/BMBRep.2017.50.3.223","article-title":"Afatinib ameliorates osteoclast differentiation and function through downregulation of RANK signaling pathways","volume":"50","author":"Ihn","year":"2017","journal-title":"BMB Rep."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.4049\/jimmunol.1100996","article-title":"Lung tumor-associated dendritic cell-derived amphiregulin increased cancer progression","volume":"187","author":"Hsu","year":"2011","journal-title":"J. Immunol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1016\/j.bbamcr.2017.06.017","article-title":"Quercetin suppresses the metastatic ability of lung cancer through inhibiting Snail-dependent Akt activation and Snail-independent ADAM9 expression pathways","volume":"1864","author":"Chang","year":"2017","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_160","doi-asserted-by":"crossref","unstructured":"Deiana, M., Dalle Carbonare, L., Serena, M., Cheri, S., Mutascio, S., Gandini, A., Innamorati, G., Lorenzi, P., Cumerlato, M., and Bertacco, J. (2020). A Potential Role of RUNX2- RUNT Domain in Modulating the Expression of Genes Involved in Bone Metastases: An In Vitro Study with Melanoma Cells. Cells, 9.","DOI":"10.3390\/cells9030751"},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.juro.2015.01.079","article-title":"Bone Metastasis in Renal Cell Carcinoma is Preprogrammed in the Primary Tumor and Caused by AKT and Integrin alpha5 Signaling","volume":"194","author":"Haber","year":"2015","journal-title":"J. Urol."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"15766","DOI":"10.18632\/oncotarget.24607","article-title":"Calcium-sensing receptor (CaSR) promotes development of bone metastasis in renal cell carcinoma","volume":"9","author":"Frees","year":"2018","journal-title":"Oncotarget"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/1476-4598-13-42","article-title":"High calcium concentration in bones promotes bone metastasis in renal cell carcinomas expressing calcium-sensing receptor","volume":"13","author":"Joeckel","year":"2014","journal-title":"Mol. Cancer"},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1016\/j.cellsig.2012.08.004","article-title":"PI3K\/Akt to GSK3beta\/beta-catenin signaling cascade coordinates cell colonization for bladder cancer bone metastasis through regulating ZEB1 transcription","volume":"24","author":"Wu","year":"2012","journal-title":"Cell Signal."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"333","DOI":"10.3892\/ijo.2014.2421","article-title":"CCL5 secreted from bone marrow stromal cells stimulates the migration and invasion of Huh7 hepatocellular carcinoma cells via the PI3K-Akt pathway","volume":"45","author":"Bai","year":"2014","journal-title":"Int. J. Oncol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"5118","DOI":"10.7150\/jca.45995","article-title":"LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis","volume":"11","author":"Ma","year":"2020","journal-title":"J. Cancer"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S1535-6108(04)00081-9","article-title":"Periostin potently promotes metastatic growth of colon cancer by augmenting cell survival via the Akt\/PKB pathway","volume":"5","author":"Bao","year":"2004","journal-title":"Cancer Cell"},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1016\/j.yexcr.2011.04.006","article-title":"Metastatic function of BMP-2 in gastric cancer cells: The role of PI3K\/AKT, MAPK, the NF-kappaB pathway, and MMP-9 expression","volume":"317","author":"Kang","year":"2011","journal-title":"Exp. Cell Res."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.yexcr.2009.10.010","article-title":"BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)\/Akt pathway","volume":"316","author":"Kang","year":"2010","journal-title":"Exp. Cell Res."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.oraloncology.2011.08.022","article-title":"Secretion of IL-6 and IL-8 from lysophosphatidic acid-stimulated oral squamous cell carcinoma promotes osteoclastogenesis and bone resorption","volume":"48","author":"Hwang","year":"2012","journal-title":"Oral Oncol."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"4716","DOI":"10.1158\/0008-5472.CAN-04-4196","article-title":"Antivascular therapy of human follicular thyroid cancer experimental bone metastasis by blockade of epidermal growth factor receptor and vascular growth factor receptor phosphorylation","volume":"65","author":"Younes","year":"2005","journal-title":"Cancer Res."},{"key":"ref_172","doi-asserted-by":"crossref","unstructured":"Smit, D.J., Cayrefourcq, L., Haider, M.T., Hinz, N., Pantel, K., Alix-Panabieres, C., and Jucker, M. (2020). High Sensitivity of Circulating Tumor Cells Derived from a Colorectal Cancer Patient for Dual Inhibition with AKT and mTOR Inhibitors. Cells, 9.","DOI":"10.3390\/cells9092129"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"2650","DOI":"10.1158\/1078-0432.CCR-15-2160","article-title":"A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor-Positive Metastatic Breast Cancer","volume":"22","author":"Ma","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1158\/1078-0432.CCR-18-0981","article-title":"Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss","volume":"25","author":"Rodrigues","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1016\/S1470-2045(17)30450-3","article-title":"Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial","volume":"18","author":"Kim","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1200\/JCO.19.00368","article-title":"Capivasertib Plus Paclitaxel Versus Placebo Plus Paclitaxel As First-Line Therapy for Metastatic Triple-Negative Breast Cancer: The PAKT Trial","volume":"38","author":"Schmid","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_177","doi-asserted-by":"crossref","unstructured":"Kan, C., Vargas, G., Pape, F.L., and Clezardin, P. (2016). Cancer Cell Colonisation in the Bone Microenvironment. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17101674"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.7314\/APJCP.2014.15.4.1503","article-title":"Medical treatment of breast cancer bone metastasis: From bisphosphonates to targeted drugs","volume":"15","author":"Erdogan","year":"2014","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.2174\/138161210791034049","article-title":"Tgf-Beta pathway as a therapeutic target in bone metastases","volume":"16","author":"Juarez","year":"2010","journal-title":"Curr. Pharm. Des."},{"key":"ref_180","doi-asserted-by":"crossref","unstructured":"Biswas, S., Nyman, J.S., Alvarez, J., Chakrabarti, A., Ayres, A., Sterling, J., Edwards, J., Rana, T., Johnson, R., and Perrien, D.S. (2011). Anti-transforming growth factor ss antibody treatment rescues bone loss and prevents breast cancer metastasis to bone. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0027090"},{"key":"ref_181","first-page":"004","article-title":"Metastatic bone disease: Pathogenesis and therapeutic options: Up-date on bone metastasis management","volume":"15","author":"Coleman","year":"2019","journal-title":"J. Bone Oncol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"TPS1109","DOI":"10.1200\/JCO.2020.38.15_suppl.TPS1109","article-title":"A phase III trial of capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer (CAPItello290)","volume":"38","author":"Schmid","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.bbcan.2018.08.001","article-title":"The next generation of PI3K-Akt-mTOR pathway inhibitors in breast cancer cohorts","volume":"1870","author":"McKenna","year":"2018","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/s12964-019-0450-3","article-title":"Distinct functions of AKT isoforms in breast cancer: A comprehensive review","volume":"17","author":"Hinz","year":"2019","journal-title":"Cell Commun. Signal."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s12964-018-0295-1","article-title":"Akt1 inhibition promotes breast cancer metastasis through EGFR-mediated \u03b2-catenin nuclear accumulation","volume":"16","author":"Li","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Hinz, N., Baranowsky, A., Horn, M., Kriegs, M., Sibbertsen, F., Smit, D.J., Clezardin, P., Lange, T., Schinke, T., and J\u00fccker, M. (2021). Knockdown of AKT3 Activates HER2 and DDR Kinases in Bone-Seeking Breast Cancer Cells, Promotes Metastasis In Vivo and Attenuates the TGF\u03b2\/CTGF Axis. Cells, 10.","DOI":"10.3390\/cells10020430"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1002\/ijc.28214","article-title":"Combined targeting of AKT and mTOR using MK-2206 and RAD001 is synergistic in the treatment of cholangiocarcinoma","volume":"133","author":"Ewald","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.7150\/jca.12452","article-title":"Vertical Targeting of AKT and mTOR as Well as Dual Targeting of AKT and MEK Signaling Is Synergistic in Hepatocellular Carcinoma","volume":"6","author":"Ewald","year":"2015","journal-title":"J. Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/10\/2287\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:59:00Z","timestamp":1760162340000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/13\/10\/2287"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,11]]},"references-count":188,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["cancers13102287"],"URL":"https:\/\/doi.org\/10.3390\/cancers13102287","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,11]]}}}