The matrix protein Fibulin-3 promotes KISS1R induced triple negative breast cancer cell invasion
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Michelle M. Noonan1, Magdalena Dragan1, Michael M. Mehta1, David A. Hess1,7, Muriel Brackstone2,4,5, Alan B. Tuck2,3,6, Navin Viswakarma8, Ajay Rana8, Andy V. Babwah9, Frederic E. Wondisford10 and Moshmi Bhattacharya1,2,4,10
1Department of Physiology and Pharmacology, The University of Western Ontario, London, ON, Canada
2Department of Oncology, The University of Western Ontario, London, ON, Canada
3Department of Pathology, The University of Western Ontario, London, ON, Canada
4Lawson Health Research Institute, The University of Western Ontario, London, ON, Canada
5Division of Surgical Oncology, The University of Western Ontario, London, ON, Canada
6The Pamela Greenaway-Kohlmeier Translational Breast Cancer Research Unit, London Regional Cancer Program, London, ON, Canada
7Krembil Centre for Stem Cell Biology, Molecular Medicine Research Group, Robarts Research Institute, London, ON, Canada
8Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA
9Department of Pediatrics, Child Health Institute of NJ, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
10Department of Medicine, Child Health Institute of NJ, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA
Moshmi Bhattacharya, email: [email protected]
Keywords: fibulin-3; kisspeptin receptor; triple-negative breast cancer; invasion; metastasis
Received: September 22, 2017 Accepted: June 13, 2018 Published: July 10, 2018
Breast cancer is a leading cause of cancer mortality. In particular, triple negative breast cancer (TNBC) comprise a heterogeneous group of basal-like tumors lacking estrogen receptor (ERα), progesterone receptor (PR) and HER2 (ErbB2). TNBC represents 15–20% of all breast cancers and occurs frequently in women under 50 years of age. Unfortunately, these patients lack targeted therapy, are typically high grade and metastatic at time of diagnosis. The mechanisms regulating metastasis remain poorly understood. We have previously shown that the kisspeptin receptor, KISS1R stimulates invasiveness of TNBC cells. In this report, we demonstrate that KISS1R signals via the secreted extracellular matrix protein, fibulin-3, to regulate TNBC invasion. We found that the fibulin-3 gene is amplified in TNBC primary tumors and that plasma fibulin-3 levels are elevated in TNBC patients compared to healthy subjects. In this study, we show that KISS1R activation increases fibulin-3 expression and secretion. We show that fibulin-3 regulates TNBC metastasis in a mouse experimental metastasis xenograft model and signals downstream of KISS1R to stimulate TNBC invasion, by activating matrix metalloproteinase 9 (MMP-9) and the MAPK pathway. These results identify fibulin-3 as a new downstream mediator of KISS1R signaling and as a potential biomarker for TNBC progression and metastasis, thus revealing KISS1R and fibulin-3 as novel drug targets in TNBC.
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