ECTS2016 Poster Presentations Cancer and bone: basic, translational and clinical (37 abstracts)
MicroRNA-30 family regulates bone tropism and osteomimicry in human breast cancer cells
Croset Martine 1 , Pantano Francesco 2 , Kan Casina 1 , Bonnelye Edith 1 , Alix-Panabieres Catherine 3 , Lecellier Charles 4 , Hong Saw-See 5 , Bartkowiak Kai 6 , Pantel Klaus 6 & Clezardin Philippe 1
1INSERM U1033, Université Lyon 1 Claude Bernard, Lyon, France; 2Medical Oncology Department, University Campus Bio-Medico, Rome, Italy; 3Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Center, Montpellier, France; 4University of Montpellier, CNRS UMR-5535, Montpellier, France; 5University of Lyon 1, INRA UMR-754, Lyon, France; 6Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Breast cancer cells that escape primary tumors disseminate to bone with high affinity at late-stage disease. Circulating breast tumor cells that invade the bone marrow (BM) express sets of deregulated genes and/or microRNAs (miRNAs) that facilitate their bone tropism and enhance engraftment of disseminated tumor cell (DTC) in BM which may subsequently induce osteolytic lesions. MiRNA transcriptomic profiling of the human breast cancer DTC cell line, BC-M1, and of the osteotropic cell line MDA-B02 let us identified drastic down-regulation of the miRNA-30 family (miRs-30), which is composed of five members (miR-30a, miR-30b, miR-30c, miR-30d and miR-30e). Genes encoding for osteotropism and osteomimicry were highly expressed in BC-M1 and MDA-B02 and were predicted in silico as being miRs-30 targets. Restoring the miRs-30 expression in MDA-B02 (MDA-B02-miRs-30) inhibited bone metastasis in a murine experimental model of human bone metastasis. Consistent with these in vivo data, miRs-30 reduced the expression of osteotropic and osteomimetic genes, ITGβ3, ITGα5 (Integrin β3, α5), CDH11 (Cadherin11), CTGF (connective tissue growth factor) and RunX2, of oncogenic genes, MTDH (Metadherin), NT5E (5′-ectonucleotidase), TNC (TenascinC) and NEDD4 (E3-ubiquitin protein ligase) and impacted negatively on tumor cell invasiveness in vitro. There was also a substantial reduction of the production of pro-osteoclastic cytokines IL-8 and IL-11 in the conditioned medium (CM) from MDA-BO2-miRs-30 (CM-miRs-30), which was associated with decreased formation of TRAP-positive multinucleated osteoclasts. Additionally, osteogenic properties of MC3T3-E1 osteoblastic cells were inhibited in the presence of CM from MDA-BO2 cells and this inhibitory effect was repressed by miRs-30 through a decreased production of the Wnt inhibitor Dkk1. Moreover, we found that low miRs-30 expression in primary tumors from patients with breast cancer was associated with poor relapse-free survival.
We conclude that miRs-30s impact negatively on BM colonization by breast cancer cells, leading to a reduction in the formation of skeletal lesions in tumor-bearing animals.
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Bone Abstracts
ISSN 2052-1219 (online)
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