[en] BACKGROUND: Mitochondrial fusion and fission proteins have been nominated as druggable targets in cancer. Whether their inhibition is efficacious in triple negative breast cancer (TNBC) that almost invariably develops chemoresistance is unknown.
METHODS: We used a combination of bioinformatics analyses of cancer genomic databases, genetic and pharmacological Optic Atrophy 1 (OPA1) inhibition, mitochondrial function and morphology measurements, micro-RNA (miRNA) profiling and formal epistatic analyses to address the role of OPA1 in TNBC proliferation, migration, and invasion in vitro and in vivo.
RESULTS: We identified a signature of OPA1 upregulation in breast cancer that correlates with worse prognosis. Accordingly, OPA1 inhibition could reduce breast cancer cells proliferation, migration, and invasion in vitro and in vivo. Mechanistically, while OPA1 silencing did not reduce mitochondrial respiration, it increased levels of miRNAs of the 148/152 family known to inhibit tumor growth and invasiveness. Indeed, these miRNAs were epistatic to OPA1 in the regulation of TNBC cells growth and invasiveness.
CONCLUSIONS: Our data show that targeted inhibition of the mitochondrial fusion protein OPA1 curtails TNBC growth and nominate OPA1 as a druggable target in TNBC.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Zamberlan, Margherita ✱; Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
Boeckx, Amandine ✱; Université de Liège - ULiège > GIGA ; Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
Muller, Florian ; Université de Liège - ULiège > Département des sciences de la vie ; Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
Vinelli, Federica; Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
Ek, Olivier ; Université de Liège - ULiège > GIGA > GIGA I3 - Cellular and Molecular Immunology ; Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
Vianello, Caterina; Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
Coart, Emeline ; Université de Liège - ULiège > GIGA > GIGA Cancer - Molecular Angiogenesis Laboratory ; Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
Shibata, Keitaro; Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
Christian, Aurélie ; Université de Liège - ULiège > GIGA > GIGA Cancer - Molecular Angiogenesis Laboratory ; Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
Grespi, Francesca; Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy
Giacomello, Marta; Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy
Struman, Ingrid ; Université de Liège - ULiège > Département des sciences de la vie ; Laboratory of molecular angiogenesis, GIGA-Research, Avenue de l'Hôpital, 1, 4020, Liège, Belgium
Scorrano, Luca ✱; Department of Biology, University of Padova, Via U. Bassi 58B, 35121, Padova, Italy. luca.scorrano@unipd.it ; Veneto Institute of Molecular Medicine, Via Orus 2, 35129, Padova, Italy. luca.scorrano@unipd.it
Herkenne, Stéphanie ✱; Université de Liège - ULiège > Département des sciences de la vie
AIRC - Associazione Italiana per la Ricerca sul Cancro [IT] Fondazione Cassa di Risparmio di Padova e Rovigo [IT] MIUR - Ministero dell'Istruzione, dell'Università e della Ricerca [IT]
Funding text :
We thank Drs. F. Caicci and F. Boldrin (EM Facility, Department of Biology, University of Padova) for EM samples preparation. We thank the GIGA imaging and mouse facility for help with the in vivo experiments (GIGA Institute, University of Li?ge).This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) IG19991 (to LS); European Research Council (ERC) FP7–282280 and European Union FP7 CIG PCIG13-GA-2013-618697; Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) FIRB RBAP11Z3YA_005 and PRIN 2017BF3PXZ, Fondazione Cariparo Progetto d’eccellenza SIGMI (to LS); SH was supported by a FP7-Cofund DTI-IMPORT, an AIRC Fellowship, Fonds Léon Frédéricq (University of Liège), by a Foundation Umberto Veronesi fellowship, by a Fonds National de la recherche scientifique (FNRS) fellowship and Fondation Belge contre le Cancer. AB was supported by a TELEVIE fellowship.
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