title: Curcuminoids block TGF-β signaling in human breast cancer cells and limit osteolysis in a murine model of breast cancer bone metastasis.
abstract: Effects of curcuminoids on breast cancer cell secretion of the bone-resorptive peptide parathyroid hormone-related protein (PTHrP) and on lytic breast cancer bone metastasis were evaluated. In vitro, transforming growth factor (TGF)-β-stimulated PTHrP secretion was inhibited by curcuminoids (IC50 = 24 μM) in MDA-MB-231 human breast cancer cells independent of effects on cell growth inhibition. Effects on TGF-β signaling revealed decreases in phospho-Smad2/3 and Ets-1 protein levels with no effect on p-38 MAPK-mediated TGF-β signaling. In vivo, mice were inoculated with MDA-MB-231 cells into the left cardiac ventricle and treated ip every other day with curcuminoids (25 or 50 mg/kg) for 21 days. Osteolytic bone lesion area was reduced up to 51% (p < 0.01). Consistent with specific effects on bone osteolysis, osteoclast number at the bone-tumor interface was reduced up to 53% (p < 0.05), while tumor area within bone was unaltered. In a separate study, tumor mass in orthotopic mammary xenografts was also unaltered by treatment. These data suggest that curcuminoids prevent TGF-β induction of PTHrP and reduce osteolytic bone destruction by blockade of Smad signaling in breast cancer cells.
authors.affiliation: Endocrinology Section, Department of Medicine, The University of Arizona, Tucson, Arizona 85724, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Wright
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Frye
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Lukefahr
authors.forename: Barbara N
authors.initials: BN
authors.lastname: Timmermann
authors.forename: Khalid S
authors.initials: KS
authors.lastname: Mohammad
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Guise
authors.forename: Janet L
authors.initials: JL
authors.lastname: Funk
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010014:Osteolysis / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D044162:Parathyroid Hormone-Related Protein; D016212:Transforming Growth Factor beta; D003474:Curcumin