COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis

Proc Natl Acad Sci U S A. 2019 Mar 19;116(12):5223-5232. doi: 10.1073/pnas.1819303116. Epub 2019 Feb 28.


Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.

Keywords: COX-2; NR4A; metastasis; prolactin; tumor-stromal communication.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / metabolism*
  • Celecoxib / pharmacology
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Male
  • Mice
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism
  • Prolactin / metabolism*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Retinoid X Receptors / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism*
  • Stromal Cells / pathology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Cyclooxygenase 2 Inhibitors
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Retinoid X Receptors
  • Prolactin
  • Cyclooxygenase 2
  • Celecoxib
  • Dinoprostone