title: Human stromal cells are required for an anti-breast cancer effect of zoledronic acid.
abstract: Previous studies suggested that bisphosphonate zoledronic acid exerts an anti-tumor effect by interacting with the microenvironment. In this study, we aimed to elucidate the mechanism behind the anti-breast cancer effect of zoledronic acid.Here we showed that zoledronic acid did not influence in vitro human breast cancer cell survival, but did affect human stromal cell survival. Breast cancer cell death in co-culture with stromal cells was analyzed in vitro by fluorescent microscopy and flowcytometry analysis. In co-culture, the addition of stromal cells to breast cancer cells induced tumor cell death by zoledronic acid, which was abolished by transforming growth factor (TGF)-β. In the in vivo chicken chorioallantoic membrane model, zoledronic acid reduced the breast cancer cells fraction per tumor only in the presence of human stromal cells. Zoledronic acid decreased TGF-β excretion by stromal cells and co-cultures. Moreover, supernatant of zoledronic acid treated stromal cells reduced phospho-Smad2 protein levels in breast cancer cells. Thus, zoledronic acid exerts an anti-breast cancer effect via stromal cells, accompanied by decreased stromal TGF-β excretion and reduced TGF-β signaling in cancer cells.
authors.affiliation: Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hilde H
authors.initials: HH
authors.lastname: Nienhuis
authors.affiliation: Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marlous
authors.initials: M
authors.lastname: Arjaans
authors.affiliation: Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hetty
authors.initials: H
authors.lastname: Timmer-Bosscha
authors.affiliation: Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Department of Medical Oncology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Carolina P
authors.initials: CP
authors.lastname: Schröder
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D050071:Bone Density Conservation Agents / Q000737:chemistry; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000378:metabolism; D018920:Coculture Techniques; D004164:Diphosphonates / Q000737:chemistry*; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells / Q000187:drug effects; D008856:Microscopy, Fluorescence; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D000077211:Zoledronic Acid
keywords: CAM model; TGF-β; breast cancer; microenvironment; zoledronic acid