TRPV2 is a novel biomarker and therapeutic target in triple negative breast cancer

// Mohamad Elbaz 1, 2, 5 , Dinesh Ahirwar 1, 2 , Zhang Xiaoli 3 , Xinyu Zhou 6 , Maryam Lustberg 4 , Mohd W. Nasser 1, 2 , Konstantin Shilo 1, 2 , Ramesh K. Ganju 1, 2 1 Department of Pathology, Wexner Medical Center, Ohio State University (OSU), Columbus, OH, USA 2 The Comprehensive Cancer Center, Ohio State University (OSU), Wexner Medical Center, Columbus, OH, USA 3 Center for Biostatistics, Ohio State University (OSU), Columbus, OH, USA 4 Department of Internal Medicine, Ohio State University (OSU), Columbus, OH, USA 5 Department of Pharmacology, Pharmacy School, Helwan University, Helwan, Egypt 6 Department of surgery, Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH, USA Correspondence to: Ramesh K. Ganju, email: Ramesh.ganju@osumc.edu Keywords: TRPV2, chemotherapy, TNBC, uptake, doxorubicin Abbreviations: Transient Receptor Potential Vanilloid type 2 (TRPV2), Triple negative Breast cancer (TNBC), Doxorubicin (Dox), CBD (cannabidiol). Received: March 24, 2016 Accepted: April 27, 2016 Epub: May 27, 2016 Published: September 11, 2018 ABSTRACT Transient receptor potential vanilloid type-2 (TRPV2) is an ion channel that is triggered by agonists like cannabidiol (CBD). Triple negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Chemotherapy is still the first line for the treatment of TNBC patients; however, TNBC usually gains rapid resistance and unresponsiveness to chemotherapeutic drugs. In this study, we found that TRPV2 protein is highly up-regulated in TNBC tissues compared to normal breast tissues. We also observed that TNBC and estrogen receptor alpha negative (ERα - ) patients with higher TRPV2 expression have significantly higher recurrence free survival compared to patients with lower TRPV2 expression especially those who were treated with chemotherapy. In addition, we showed that TRPV2 overexpression or activation by CBD significantly increased doxorubicin (DOX) uptake and apoptosis in TNBC cells. The induction of DOX uptake was abrogated by TRPV2 blocking or downregulation. In vivo mouse model studies showed that the TNBC tumors derived from CBD+DOX treated mice have significantly reduced weight and increased apoptosis compared to those treated with CBD or DOX alone. Overall, our studies for the first time revealed that TRPV2 might be a good prognostic marker for TNBC and ERα - breast cancer patient especially for those who are treated with chemotherapy. In addition, TRPV2 activation could be a novel therapeutic strategy to enhance the uptake and efficacy of chemotherapy in TNBC patients.