Oncotarget

Research Papers:

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

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 _

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Oncotarget. 2018; 9:23208-23219. https://doi.org/10.18632/oncotarget.25292

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Abstract

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

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.


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