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PKD1 is a potential biomarker and therapeutic target in triple-negative breast cancer

2018; Impact Journals LLC; Volume: 9; Issue: 33 Linguagem: Inglês

10.18632/oncotarget.25292

1949-2553

Caroline Spasojevic, Elisabetta Marangoni, Sophie Vacher, Franck Assayag, Didier Meseure, Sophie Château‐Joubert, Martine Humbert, Manale Karam, Jean Marc Ricort, Christian Auclair, Marie Regairaz, Ivan Bièche,

Cancer-related gene regulation

// Caroline Spasojevic 1, 2 , Elisabetta Marangoni 3 , Sophie Vacher 1 , Franck Assayag 3 , Didier Meseure 4 , Sophie Château-Joubert 5 , Martine Humbert 6 , Manale Karam 2, 7 , Jean Marc Ricort 2 , Christian Auclair 6, 8 , Marie Regairaz 2 and Ivan Bièche 1 1 Pharmacogenomics Unit, Department of Genetics, Institut Curie, Paris, France 2 LBPA, CNRS UMR8113, ENS Paris-Saclay, Paris-Saclay University, Cachan, France 3 Translational Research Department, Institut Curie, PSL Research University, Paris, France 4 Department of Pathology, Institut Curie, Paris, France 5 BioPôle Alfort, Ecole Nationale Vétérinaire d’Alfort, Maisons Alfort, France 6 AB Science SA, Paris, France 7 Cancer Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar 8 Biology Department, ENS Paris-Saclay, Paris-Saclay University, Cachan, France Correspondence to: Ivan Bièche, email: ivan.bieche@curie.fr Keywords: triple-negative breast cancer; protein kinase D1; PKD; PKC Received: September 26, 2017 Accepted: April 03, 2018 Published: May 01, 2018 ABSTRACT Protein Kinase D1 (PKD1) is a serine/threonine kinase encoded by the PRKD1 gene. PKD1 has been previously shown to be a prognostic factor in ERα+ tamoxifen-resistant breast tumors and PKD1 overexpression confers estrogen independence to ERα+ MCF7 cells. In the present study, our goal was to determine whether PKD1 is a prognostic factor and/or a relevant therapeutic target in breast cancer. We analyzed PRKD1 mRNA levels in 527 primary breast tumors. We found that high PRKD1 mRNA levels were significantly and independently associated with a low metastasis-free survival in the whole breast cancer population and in the triple-negative breast cancer (TNBC) subtype specifically. High PRKD1 mRNA levels were also associated with a low overall survival in TNBC. We identified novel PKD1 inhibitors and assessed their antitumor activity in vitro in TNBC cell lines and in vivo in a TNBC patient-derived xenograft (PDX) model. Pharmacological inhibition and siRNA-mediated depletion of PKD1 reduced colony formation in MDA-MB-436 TNBC cells. PKD1 inhibition also reduced tumor growth in vivo in a TNBC PDX model. Together, these results establish PKD1 as a poor prognostic factor and a potential therapeutic target in TNBC.