RT Journal Article SR Electronic T1 PTHrP Regulates Angiogenesis and Bone Resorption via VEGF Expression JF Anticancer Research JO Anticancer Res FD International Institute of Anticancer Research SP 2755 OP 2767 VO 30 IS 7 A1 SACHIKO ISOWA A1 TSUYOSHI SHIMO A1 SOICHIRO IBARAGI A1 NAITO KURIO A1 TATSUO OKUI A1 KIMINORI MATSUBARA A1 NUR MOHAMMAD MONSUR HASSAN A1 KOJI KISHIMOTO A1 AKIRA SASAKI YR 2010 UL http://ar.iiarjournals.org/content/30/7/2755.abstract AB Background: Parathyroid hormone-related protein (PTHrP) is a key regulator of osteolytic metastasis of breast cancer (BC) cells, but its targets and mechanisms of action are not fully understood. This study investigated whether/how PTHrP (1-34) signaling regulates expression of vascular endothelial growth factor (VEGF) produced by BC cells. Materials and Methods: A mouse model of bone metastasis was prepared by inoculating mice with tumour cell suspensions of the human BC cell line MDA-MB-231 via the left cardiac ventricle. VEGF expression was examined by Western blot and real-time RT-PCR analysis, as well as by confocal microscopy in the bone microenvironment. Results: PTHrP was expressed in cancer cells producing PTH/PTHrP receptor and VEGF that had invaded the bone marrow, and PTHrP was up-regulated VEGF in MDA-MB-231 in vitro. The culture medium conditioned by PTHrP-treated MDA-MB-231 cells stimulated angiogenesis and osteoclastogenesis compared with control medium, giving a response that was inhibited by VEGF-neutralizing antibody treatment. Inhibition of protein kinase C (PKC) prevented PTHrP-induced extracellular signal-regulated kinase (ERK1/2) and p38 activation, and PTHrP-induced VEGF expression. Conclusion: PTHrP plays an important role in modulating the angiogenic and bone osteolytic actions of VEGF through PKC-dependent activation of an ERK1/2 and p38 signaling pathway during bone metastasis by breast cancer cells.