LRP5 regulates the expression of STK40, a new potential target in triple-negative breast cancers

// Sylvie Maubant 1, * , Tania Tahtouh 1, * , Amelie Brisson 1 , Virginie Maire 1 , Fariba Nemati 2 , Bruno Tesson 1, 3 , Mengliang Ye 1 , Guillem Rigaill 4, 5 , Maite Noizet 1 , Aurelie Dumont 1 , David Gentien 6 , Berengere Marty-Prouvost 1 , Leanne de Koning 7 , Sardar Faisal Mahmood 1 , Didier Decaudin 2 , Francisco Cruzalegui 8 , Gordon C. Tucker 8 , Sergio Roman-Roman 9 and Thierry Dubois 1 1 Institut Curie, PSL Research University, Translational Research Department, Breast Cancer Biology Group, Paris, France 2 Institut Curie, PSL Research University, Translational Research Department, Preclinical Investigation Laboratory, Paris, France 3 Institut Curie, PSL Research University, INSERM U900, Paris, France 4 Institute of Plant Sciences Paris-Saclay (IPS2), UMR 9213/UMR 1403, CNRS, INRA, Universite Paris-Sud, Universite d’Evry, Universite Paris-Diderot, Sorbonne Paris-Cite, Orsay, France 5 Laboratoire de Mathematiques et Modelisation d’Evry (LaMME), Universite d’Evry Val d’Essonne, UMR CNRS 8071, ENSIIE, USC INRA, Evry, France 6 Institut Curie, PSL Research University, Translational Research Department, Genomics Platform, Paris, France 7 Institut Curie, PSL Research University, Translational Research Department, Reverse-Phase Protein Array Platform, Paris, France 8 Oncology Research and Development Unit, Institut de Recherches SERVIER, Croissy-Sur-Seine, France 9 Institut Curie, PSL Research University, Translational Research Department, Paris, France * These authors have contributed equally to this work Correspondence to: Thierry Dubois, email: thierry.dubois@curie.fr Keywords: triple-negative breast cancer; LRP5; LRP6; STK40; targeted therapy Received: January 18, 2018      Accepted: April 04, 2018      Published: April 27, 2018 ABSTRACT Triple-negative breast cancers (TNBCs) account for a large proportion of breast cancer deaths, due to the high rate of recurrence from residual, resistant tumor cells. New treatments are needed, to bypass chemoresistance and improve survival. The WNT pathway, which is activated in TNBCs, has been identified as an attractive pathway for treatment targeting. We analyzed expression of the WNT coreceptors LRP5 and LRP6 in human breast cancer samples. As previously described, LRP6 was overexpressed in TNBCs. However, we also showed, for the first time, that LRP5 was overexpressed in TNBCs too. The knockdown of LRP5 or LRP6 decreased tumorigenesis in vitro and in vivo , identifying both receptors as potential treatment targets in TNBC. The apoptotic effect of LRP5 knockdown was more robust than that of LRP6 depletion. We analyzed and compared the transcriptomes of cells depleted of LRP5 or LRP6, to identify genes specifically deregulated by LRP5 potentially implicated in cell death. We identified serine/threonine kinase 40 (STK40) as one of two genes specifically downregulated soon after LRP5 depletion. STK40 was found to be overexpressed in TNBCs, relative to other breast cancer subtypes, and in various other tumor types. STK40 depletion decreased cell viability and colony formation, and induced the apoptosis of TNBC cells. In addition, STK40 knockdown impaired growth in an anchorage-independent manner in vitro and slowed tumor growth in vivo . These findings identify the largely uncharacterized putative protein kinase STK40 as a novel candidate treatment target for TNBC.