PKD1 is a potential biomarker and therapeutic target in triple-negative breast cancer
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Caroline Spasojevic1,2, Elisabetta Marangoni3, Sophie Vacher1, Franck Assayag3, Didier Meseure4, Sophie Château-Joubert5, Martine Humbert6, Manale Karam2,7, Jean Marc Ricort2, Christian Auclair6,8, Marie Regairaz2 and Ivan Bièche1
1Pharmacogenomics Unit, Department of Genetics, Institut Curie, Paris, France
2LBPA, CNRS UMR8113, ENS Paris-Saclay, Paris-Saclay University, Cachan, France
3Translational Research Department, Institut Curie, PSL Research University, Paris, France
4Department of Pathology, Institut Curie, Paris, France
5BioPôle Alfort, Ecole Nationale Vétérinaire d’Alfort, Maisons Alfort, France
6AB Science SA, Paris, France
7Cancer Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar
8Biology Department, ENS Paris-Saclay, Paris-Saclay University, Cachan, France
Ivan Bièche, email: [email protected]
Keywords: triple-negative breast cancer; protein kinase D1; PKD; PKC
Received: September 26, 2017 Accepted: April 03, 2018 Published: May 01, 2018
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.
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