BACKGROUND: PTHrP, a mediator of humoral hypercalcemia of malignancy, is considered as a potential activator to induce breast cancer cells metastasizing to bone. However, recent clinical evidences and basal research results prove that PTHrP expression in primary tumors indicates good prognosis. BMP-6, as a member of TGF-β superfamily, is closely correlated with tumor differentiation and skeletal metastasis. PURPOSE: These experiments were designed to investigate the molecular mechanism of PTHrP regulating BMP-6 in breast cancer cells. METHODS AND RESULTS: Through detecting mRNA expression levels of PTHrP and BMP-6 in 35 breast cancer specimens, the two genes' expression were proved to be negatively correlated. Moreover, PTHrP (1-40), instead of PTHrP (107-139), inhibited BMP-6 mRNA expression in MCF-7 cells, indicating that PTHrP exerts its effect on BMP-6 through membranous PTHrP receptor. Inhibitors against signaling pathways downstream of PTHrP were utilized. H89, the PKA pathway inhibitor, eliminated the inhibitory effect of PTHrP on BMP-6. In addition, silencing of BMP-6 strengthened the antimitogenic effect of PTHrP. CONCLUSIONS: These results suggest that PTHrP acts as the upstream molecule of BMP-6, and exerts antimitogenic effect via reducing BMP-6 mRNA expression through PKA signaling pathway in breast cancer cells.
BACKGROUND:PTHrP, a mediator of humoral hypercalcemia of malignancy, is considered as a potential activator to induce breast cancer cells metastasizing to bone. However, recent clinical evidences and basal research results prove that PTHrP expression in primary tumors indicates good prognosis. BMP-6, as a member of TGF-β superfamily, is closely correlated with tumor differentiation and skeletal metastasis. PURPOSE: These experiments were designed to investigate the molecular mechanism of PTHrP regulating BMP-6 in breast cancer cells. METHODS AND RESULTS: Through detecting mRNA expression levels of PTHrP and BMP-6 in 35 breast cancer specimens, the two genes' expression were proved to be negatively correlated. Moreover, PTHrP (1-40), instead of PTHrP (107-139), inhibited BMP-6 mRNA expression in MCF-7 cells, indicating that PTHrP exerts its effect on BMP-6 through membranous PTHrP receptor. Inhibitors against signaling pathways downstream of PTHrP were utilized. H89, the PKA pathway inhibitor, eliminated the inhibitory effect of PTHrP on BMP-6. In addition, silencing of BMP-6 strengthened the antimitogenic effect of PTHrP. CONCLUSIONS: These results suggest that PTHrP acts as the upstream molecule of BMP-6, and exerts antimitogenic effect via reducing BMP-6 mRNA expression through PKA signaling pathway in breast cancer cells.
Authors: J J Wysolmerski; S Cormier; W M Philbrick; P Dann; J P Zhang; J Roume; A L Delezoide; C Silve Journal: J Clin Endocrinol Metab Date: 2001-04 Impact factor: 5.958
Authors: J Southby; M W Kissin; J A Danks; J A Hayman; J M Moseley; M A Henderson; R C Bennett; T J Martin Journal: Cancer Res Date: 1990-12-01 Impact factor: 12.701
Authors: Michael A Henderson; Janine A Danks; John L Slavin; Graham B Byrnes; Peter F M Choong; John B Spillane; John L Hopper; T John Martin Journal: Cancer Res Date: 2006-02-15 Impact factor: 12.701
Authors: A B Abou-Samra; H Jüppner; T Force; M W Freeman; X F Kong; E Schipani; P Urena; J Richards; J V Bonventre; J T Potts Journal: Proc Natl Acad Sci U S A Date: 1992-04-01 Impact factor: 11.205