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ResearchIn-Press PreviewOncology Free access | 10.1172/JCI142677

Inhibition of relaxin autocrine signaling confers therapeutic vulnerability in ovarian cancer

Helen E. Burston,1 Oliver A. Kent,1 Laudine Communal,2 Molly L. Udaskin,1 Ren X. Sun,1 Kevin R. Brown,3 Euihye Jung,4 Kyle E. Francis,1 Jose La Rose,1 Joshua K. Lowitz,5 Ronny Drapkin,4 Anne-Marie Mes-Masson,6 and Robert Rottapel7

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Burston, H. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Kent, O. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Communal, L. in: JCI | PubMed | Google Scholar |

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Udaskin, M. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Sun, R. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Brown, K. in: JCI | PubMed | Google Scholar |

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Jung, E. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Francis, K. in: JCI | PubMed | Google Scholar |

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by La Rose, J. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Lowitz, J. in: JCI | PubMed | Google Scholar

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Drapkin, R. in: JCI | PubMed | Google Scholar |

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Mes-Masson, A. in: JCI | PubMed | Google Scholar |

1Princess Margaret Cancer Centre, University Health Network, Toronto, Canada

2Medical Oncology, University of Montreal, Montreal, Canada

3Banting and Best Department of Medical Research, Donnelly Centre for Cellul, University of Toronto, Toronto, Canada

4Penn Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, United States of America

5Antibody Development, Antibody Solutions, Santa Clara, United States of America

6Department of Medicine, University of Montreal, Montreal, Canada

7Department of Medical Biophysics, Department of Immunology, University of Toronto, Toronto, Canada

Find articles by Rottapel, R. in: JCI | PubMed | Google Scholar

Published February 9, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI142677.
Copyright © 2021, American Society for Clinical Investigation
Published February 9, 2021 - Version history
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Abstract

Ovarian cancer (OC) is the most deadly gynaecological malignancy with unmet clinical need for new therapeutic approaches. The relaxin peptide is a pleiotropic hormone with reproductive functions in the ovary. Relaxin induces aggressive cell growth in several types of cancer, but the role of relaxin in OC is poorly understood. Here, we demonstrate that relaxin and its associated G-protein coupled receptor RXFP1 form an autocrine signaling loop essential for OC in vivo tumorigenesis, cell proliferation and viability. We have found that relaxin signaling activates expression of pro-oncogenic pathways including RHO, MAPK, Wnt, and Notch. We find that relaxin is detectable in OC tumors, ascites and serum. Further, inflammatory cytokines IL-6 and TNF-α activate transcription of relaxin via recruitment of STAT3 and NFκB to the proximal promoter initiating an autocrine feedback loop that potentiates expression. Inhibition of RXFP1 or relaxin increases cisplatin sensitivity of OC cell lines and abrogates in vivo tumor formation. Finally, we demonstrate that a relaxin neutralizing antibody reduces OC cell viability and sensitizes cells to cisplatin. Collectively, targeting relaxin-RXFP1 signaling offers a potential new therapeutic strategy for OC.

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graphical abstract
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  • Version 1 (February 9, 2021): In-Press Preview
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