title: An MMP13-selective inhibitor delays primary tumor growth and the onset of tumor-associated osteolytic lesions in experimental models of breast cancer.
abstract: We investigated the effects of the matrix metalloproteinase 13 (MMP13)-selective inhibitor, 5-(4-{4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]phenoxy}phenoxy)-5-(2-methoxyethyl) pyrimidine-2,4,6(1H,3H,5H)-trione (Cmpd-1), on the primary tumor growth and breast cancer-associated bone remodeling using xenograft and syngeneic mouse models. We used human breast cancer MDA-MB-231 cells inoculated into the mammary fat pad and left ventricle of BALB/c Nu/Nu mice, respectively, and spontaneously metastasizing 4T1.2-Luc mouse mammary cells inoculated into mammary fat pad of BALB/c mice. In a prevention setting, treatment with Cmpd-1 markedly delayed the growth of primary tumors in both models, and reduced the onset and severity of osteolytic lesions in the MDA-MB-231 intracardiac model. Intervention treatment with Cmpd-1 on established MDA-MB-231 primary tumors also significantly inhibited subsequent growth. In contrast, no effects of Cmpd-1 were observed on soft organ metastatic burden following intracardiac or mammary fat pad inoculations of MDA-MB-231 and 4T1.2-Luc cells respectively. MMP13 immunostaining of clinical primary breast tumors and experimental mice tumors revealed intra-tumoral and stromal expression in most tumors, and vasculature expression in all. MMP13 was also detected in osteoblasts in clinical samples of breast-to-bone metastases. The data suggest that MMP13-selective inhibitors, which lack musculoskeletal side effects, may have therapeutic potential both in primary breast cancer and cancer-induced bone osteolysis.
authors.affiliation: St. Vincent's Institute of Medical Research, St. Vincent's Hospital, Melbourne, Australia. manisha@medstv.unimelb.edu.au
authors.forename: Manisha
authors.initials: M
authors.lastname: Shah
authors.forename: Dexing
authors.initials: D
authors.lastname: Huang
authors.forename: Tony
authors.initials: T
authors.lastname: Blick
authors.forename: Andrea
authors.initials: A
authors.lastname: Connor
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Reiter
authors.forename: Joel R
authors.initials: JR
authors.lastname: Hardink
authors.forename: Conor C
authors.initials: CC
authors.lastname: Lynch
authors.forename: Mark
authors.initials: M
authors.lastname: Waltham
authors.forename: Erik W
authors.initials: EW
authors.lastname: Thompson
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000150:complications* / Q000201:enzymology / Q000473:pathology* / Q000517:prevention & control; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010014:Osteolysis / Q000201:enzymology / Q000209:etiology* / Q000473:pathology*; D011480:Protease Inhibitors / Q000097:blood / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D003402:Creatine Kinase; D053509:Matrix Metalloproteinase 13