miRNA-30 Family Members Inhibit Breast Cancer Invasion, Osteomimicry, and Bone Destruction by Directly Targeting Multiple Bone Metastasis-Associated Genes.

Autor:	Croset M; INSERM, UMR_S1033, University Lyon 1, Lyon, France., Pantano F; INSERM, UMR_S1033, University Lyon 1, Lyon, France.; Medical Oncology Department, Campus Bio-Medico University of Rome, Rome, Italy., Kan CWS; INSERM, UMR_S1033, University Lyon 1, Lyon, France., Bonnelye E; INSERM, UMR_S1033, University Lyon 1, Lyon, France., Descotes F; Service de Biochimie Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France., Alix-Panabières C; Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre, Montpellier, France., Lecellier CH; Université Montpellier 1, Montpellier, France., Bachelier R; INSERM, UMR_S1033, University Lyon 1, Lyon, France., Allioli N; Institut des Sciences Pharmaceutiques et Biologiques (ISPB)-Faculté de Pharmacie de Lyon, University Claude Bernard Lyon 1. Centre de Recherche en Cancérologie de Lyon, Inserm U1052, CNRS UMR5286, Lyon, France., Hong SS; University Lyon 1, UMR 754-INRA-EPHE, Lyon, France., Bartkowiak K; Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany., Pantel K; Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany., Clézardin P; INSERM, UMR_S1033, University Lyon 1, Lyon, France. philippe.clezardin@inserm.fr.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2018 Sep 15; Vol. 78 (18), pp. 5259-5273. Date of Electronic Publication: 2018 Jul 24.
DOI:	10.1158/0008-5472.CAN-17-3058
Abstrakt:	miRNAs are master regulators of gene expression that play key roles in cancer metastasis. During bone metastasis, metastatic tumor cells must rewire their biology and express genes that are normally expressed by bone cells (a process called osteomimicry), which endow tumor cells with full competence for outgrowth in the bone marrow. Here, we establish miR-30 family members miR-30a, miR-30b, miR-30c, miR-30d, and miR-30e as suppressors of breast cancer bone metastasis that regulate multiple pathways, including osteomimicry. Low expression of miR-30 in primary tumors from patients with breast cancer were associated with poor relapse-free survival. In addition, estrogen receptor (ER)-negative/progesterone receptor (PR)-negative breast cancer cells expressed lower miR-30 levels than their ER/PR-positive counterparts. Overexpression of miR-30 in ER/PR-negative breast cancer cells resulted in the reduction of bone metastasis burden in vivo In vitro , miR-30 did not affect tumor cell proliferation, but did inhibit tumor cell invasion. Furthermore, overexpression of miR-30 restored bone homeostasis by reversing the effects of tumor cell-conditioned medium on osteoclastogenesis and osteoblastogenesis. A number of genes associated with osteoclastogenesis stimulation ( IL8, IL11 ), osteoblastogenesis inhibition ( DKK-1 ), tumor cell osteomimicry ( RUNX2, CDH11 ), and invasiveness ( CTGF, ITGA5, ITGB3 ) were identified as targets for repression by miR-30. Among these genes, silencing CDH11 or ITGA5 in ER-/PR-negative breast cancer cells recapitulated inhibitory effects of miR-30 on skeletal tumor burden in vivo Overall, our findings provide evidence that miR-30 family members employ multiple mechanisms to impede breast cancer bone metastasis and may represent attractive targets for therapeutic intervention. Significance: These findings suggest miR-30 family members may serve as an effective means to therapeutically attenuate metastasis in triple-negative breast cancer. Cancer Res; 78(18); 5259-73. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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