Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer

J Clin Invest. 2014 Sep;124(9):3901-12. doi: 10.1172/JCI73777. Epub 2014 Aug 18.


Breast involution following pregnancy has been implicated in the high rates of metastasis observed in postpartum breast cancers; however, it is not clear how this remodeling process promotes metastasis. Here, we demonstrate that human postpartum breast cancers have increased peritumor lymphatic vessel density that correlates with increased frequency of lymph node metastases. Moreover, lymphatic vessel density was increased in normal postpartum breast tissue compared with tissue from nulliparous women. In rodents, mammary lymphangiogenesis was upregulated during weaning-induced mammary gland involution. Furthermore, breast cancer cells exposed to the involuting mammary microenvironment acquired prolymphangiogenic properties that contributed to peritumor lymphatic expansion, tumor size, invasion, and distant metastases. Finally, in rodent models of postpartum breast cancer, cyclooxygenase-2 (COX-2) inhibition during the involution window decreased normal mammary gland lymphangiogenesis, mammary tumor-associated lymphangiogenesis, tumor cell invasion into lymphatics, and metastasis. Our data indicate that physiologic COX-2-dependent lymphangiogenesis occurs in the postpartum mammary gland and suggest that tumors within this mammary microenvironment acquire enhanced prolymphangiogenic activity. Further, our results suggest that the prolymphangiogenic microenvironment of the postpartum mammary gland has potential as a target to inhibit metastasis and suggest that further study of the therapeutic efficacy of COX-2 inhibitors in postpartum breast cancer is warranted.

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
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology*
  • Celecoxib
  • Cyclooxygenase 2 / physiology*
  • Dinoprostone / biosynthesis
  • Disease Models, Animal
  • Female
  • Humans
  • Lymphangiogenesis / physiology*
  • Lymphatic Metastasis
  • Lymphatic Vessels / pathology
  • Mice
  • Mice, Inbred BALB C
  • Pregnancy
  • Puerperal Disorders / pathology*
  • Pyrazoles / pharmacology
  • Sulfonamides / pharmacology
  • Tumor Microenvironment


  • Pyrazoles
  • Sulfonamides
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Celecoxib
  • Dinoprostone