Proliferation of estrogen receptor-alpha-positive mammary epithelial cells is restrained by transforming growth factor-beta1 in adult mice

Am J Pathol. 2005 Aug;167(2):409-17. doi: 10.1016/s0002-9440(10)62985-9.


Transforming growth factor (TGF)-beta1 is a potent inhibitor of mammary epithelial proliferation. In human breast, estrogen receptor (ER)-alpha cells rarely co-localize with markers of proliferation, but their increased frequency correlates with breast cancer risk. To determine whether TGF-beta1 is necessary for the quiescence of ER-alpha-positive populations, we examined mouse mammary epithelial glands at estrus. Approximately 35% of epithelial cells showed TGF-beta1 activation, which co-localized with nuclear receptor-phosphorylated Smad 2/3, indicating that TGF-beta signaling is autocrine. Nuclear Smad co-localized with nuclear ER-alpha. To test whether TGF-beta inhibits proliferation, we examined genetically engineered mice with different levels of TGF-beta1. ER-alpha co-localization with markers of proliferation (ie, Ki-67 or bromodeoxyuridine) at estrus was significantly increased in the mammary glands of Tgf beta1 C57/bl/129SV heterozygote mice. This relationship was maintained after pregnancy but was absent at puberty. Conversely, mammary epithelial expression of constitutively active TGF-beta1 via the MMTV promoter suppressed proliferation of ER-alpha-positive cells. Thus, TGF-beta1 activation functionally restrains ER-alpha-positive cells from proliferating in adult mammary gland. Accordingly, we propose that TGF-beta1 dysregulation may promote proliferation of ER-alpha-positive cells associated with breast cancer risk in humans.

Publication types

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

MeSH terms

  • Animals
  • Cell Proliferation*
  • Crosses, Genetic
  • DNA-Binding Proteins / metabolism
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology*
  • Estrogen Receptor alpha / metabolism*
  • Estrus / metabolism
  • Female
  • Heterozygote
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphorylation
  • Smad2 Protein
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*
  • Transforming Growth Factor beta1


  • DNA-Binding Proteins
  • Estrogen Receptor alpha
  • Smad2 Protein
  • Smad2 protein, mouse
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1