G Protein Coupled Receptor Kinase 3 Regulates Breast Cancer Migration, Invasion, and Metastasis

  • PLoS One. 2016 Apr 6;11(4):e0152856. doi: 10.1371/journal.pone.0152856.
Matthew J Billard  1 ,  David J Fitzhugh  1 ,  Joel S Parker  2  3 ,  Jaime M Brozowski  4 ,  Marcus W McGinnis  1 ,  Roman G Timoshchenko  1 ,  D Stephen Serafin  1 ,  Ruth Lininger  3  5 ,  Nancy Klauber-Demore  3  6 ,  Gary Sahagian  7 ,  Young K Truong  8 ,  Maria F Sassano  9 ,  Jonathan S Serody  3  10 ,  Teresa K Tarrant  1  3  4
Affiliations
  • 1. Thurston Arthritis Research Center and the Department of Medicine, Division of Rheumatology, Allergy, and Immunology, University of North Carolina, Chapel Hill, NC 27599, United States of America.
  • 2. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, United States of America.
  • 3. Lineberger Comprehensive Cancer Center, University of North Carolina Chapel Hill, NC 27599, United States of America.
  • 4. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, 27599, United States of America.
  • 5. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, United States of America.
  • 6. Department of Surgery, Division of Surgical Oncology, University of North Carolina, Chapel Hill, NC 27599, United States of America.
  • 7. Department of Developmental, Molecular & Chemical Biology, Tufts University, Medford, MA 02155, United States of America.
  • 8. Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, United States of America.
  • 9. Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, United States of America.
  • 10. Department of Medicine, Division of Hematology Oncology, University of North Carolina, Chapel Hill NC, 27599, United States of America.
PMID: 27049755 DOI: 10.1371/journal.pone.0152856
Abstract

Triple negative breast Cancer (TNBC) is a heterogeneous disease that has a poor prognosis and limited treatment options. Chemokine Receptor interactions are important modulators of breast Cancer metastasis; however, it is now recognized that quantitative surface expression of one important Chemokine Receptor, CXCR4, may not directly correlate with metastasis and that its functional activity in breast Cancer may better inform tumor pathogenicity. G protein coupled receptor kinase 3 (GRK3) is a negative regulator of CXCR4 activity, and we show that GRK expression correlates with tumorigenicity, molecular subtype, and metastatic potential in human tumor microarray analysis. Using established human breast Cancer cell lines and an immunocompetent in vivo mouse model, we further demonstrate that alterations in GRK3 expression levels in tumor cells directly affect migration and invasion in vitro and the establishment of distant metastasis in vivo. The effects of GRK3 modulation appear to be specific to chemokine-mediated migration behaviors without influencing tumor cell proliferation or survival. These data demonstrate that GRK3 dysregulation may play an important part in TNBC metastasis.