Uterine double-conditional inactivation of Smad2 and Smad3 in mice causes endometrial dysregulation, infertility, and uterine cancer

Proc Natl Acad Sci U S A. 2019 Feb 26;116(9):3873-3882. doi: 10.1073/pnas.1806862116. Epub 2019 Jan 16.


SMAD2 and SMAD3 are downstream proteins in the transforming growth factor-β (TGF β) signaling pathway that translocate signals from the cell membrane to the nucleus, bind DNA, and control the expression of target genes. While SMAD2/3 have important roles in the ovary, we do not fully understand the roles of SMAD2/3 in the uterus and their implications in the reproductive system. To avoid deleterious effects of global deletion, and given previous data showing redundant function of Smad2 and Smad3, a double-conditional knockout was generated using progesterone receptor-cre (Smad2/3 cKO) mice. Smad2/3 cKO mice were infertile due to endometrial hyperproliferation observed as early as 6 weeks of postnatal life. Endometrial hyperplasia worsened with age, and all Smad2/3 cKO mice ultimately developed bulky endometrioid-type uterine cancers with 100% mortality by 8 months of age. The phenotype was hormone-dependent and could be prevented with removal of the ovaries at 6 weeks of age but not at 12 weeks. Uterine tumor epithelium was associated with decreased expression of steroid biosynthesis genes, increased expression of inflammatory response genes, and abnormal expression of cell cycle checkpoint genes. Our results indicate the crucial role of SMAD2/3 in maintaining normal endometrial function and confirm the hormone-dependent nature of SMAD2/3 in the uterus. The hyperproliferation of the endometrium affected both implantation and maintenance of pregnancy. Our findings generate a mouse model to study the roles of SMAD2/3 in the uterus and serve to provide insight into the mechanism by which the endometrium can escape the plethora of growth regulatory proteins.

Keywords: TGF β signaling; endometrial cancer; female reproduction; knockout mouse; uterine hyperplasia.

Publication types

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

MeSH terms

  • Animals
  • Carcinogenesis / genetics
  • Cell Proliferation / genetics
  • Endometrium / metabolism
  • Endometrium / pathology
  • Female
  • Gene Expression Regulation / genetics
  • Humans
  • Infertility / genetics*
  • Infertility / pathology
  • Mice
  • Mice, Knockout
  • Pregnancy
  • Receptors, Progesterone / genetics
  • Smad2 Protein / genetics*
  • Smad3 Protein / genetics*
  • Uterine Neoplasms / genetics*
  • Uterine Neoplasms / pathology
  • Uterus / metabolism
  • Uterus / pathology


  • Receptors, Progesterone
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse