Prolactin and Transforming Growth Factor-Beta Signaling Exert Opposing Effects on Mammary Gland Morphogenesis, Involution, and the Akt-forkhead Pathway

Mol Endocrinol. 2004 May;18(5):1171-84. doi: 10.1210/me.2003-0345. Epub 2004 Feb 12.

Abstract

Both prolactin (PRL) and TGF-beta regulate cell survival in mammary epithelial cells, but their mechanisms of interactions are not known. In primary mammary epithelial cells and the HC11 mouse mammary epithelial cell line, PRL prevented TGF-beta-induced apoptosis, as measured by terminal deoxynucleotidyltransferase dUTP nick-end labeling staining and caspase-3 activation. This effect depended on phosphatidyl inositol triphosphate kinase (PI3K). PI3K activates a downstream serine/threonine kinase, Akt; therefore, we investigated the role of Akt in the interaction between PRL and TGF-beta signaling. Akt activity was inhibited by TGF-beta over a 20- to 60-min time course. In TGF-beta-treated cells, PRL disinhibited Akt in a PI3K-dependent manner. Expression of dominant negative Akt blocked the protective effect of PRL in TGF-beta-induced apoptosis. Transgenic mice overexpressing a dominant-negative TGF-beta type II receptor (DNIIR) in the mammary epithelium undergo hyperplastic alveolar development, and this effect was PRL dependent. Involution in response to teat sealing was slowed by overexpression of DNIIR; furthermore, Akt and forkhead phosphorylation increased in the sealed mammary glands of DNIIR mice. Thus, Akt appears to be an essential component of the interaction between PRL and TGF-beta signaling in mammary epithelial cells both in vitro and in vivo.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • Female
  • Mammary Glands, Animal / growth & development
  • Mammary Glands, Animal / metabolism*
  • Mice
  • Mice, Transgenic
  • Morphogenesis / drug effects
  • Morphogenesis / physiology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Prolactin / pharmacology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / physiology*
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Proto-Oncogene Proteins
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Prolactin
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Receptor, Transforming Growth Factor-beta Type II