p38γ mitogen-activated protein kinase (MAPK) confers breast cancer hormone sensitivity by switching estrogen receptor (ER) signaling from classical to nonclassical pathway via stimulating ER phosphorylation and c-Jun transcription

J Biol Chem. 2012 Apr 27;287(18):14681-91. doi: 10.1074/jbc.M112.349357. Epub 2012 Mar 7.

Abstract

Estrogen receptor (ER) α promotes breast cancer growth by regulating gene expression through classical estrogen response element (ERE) binding and nonclassical (interaction with c-Jun at AP-1 sites) pathways. ER is the target for anti-estrogens such as tamoxifen (TAM). However, the potential for classical versus nonclassical ER signaling to influence hormone sensitivity is not known. Moreover, anti-estrogens frequently activate several signaling cascades besides the target ER, and the implications of these "off-target" signaling events have not been explored. Here, we report that p38γ MAPK is selectively activated by treatment with TAM. This results in both phosphorylation of ER at Ser-118 and stimulation of c-Jun transcription, thus switching ER signaling from the classical to the nonclassical pathway leading to increased hormone sensitivity. Unexpectedly, phosphorylation at Ser-118 is required for ER to bind both p38γ and c-Jun, thereby promoting ER relocation from ERE to AP-1 promoter sites. Thus, ER/Ser-118 phosphorylation serves as a central mechanism by which p38γ regulates signaling transduction of ER with its inhibitor TAM.

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

  • Antineoplastic Agents, Hormonal / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • Enzyme Activation / genetics
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism*
  • Female
  • Humans
  • MAP Kinase Signaling System*
  • Mitogen-Activated Protein Kinase 12 / genetics
  • Mitogen-Activated Protein Kinase 12 / metabolism*
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Proto-Oncogene Proteins c-jun / biosynthesis*
  • Proto-Oncogene Proteins c-jun / genetics
  • Response Elements*
  • Tamoxifen / pharmacology
  • Transcription, Genetic*

Substances

  • Antineoplastic Agents, Hormonal
  • Estrogen Receptor alpha
  • Proto-Oncogene Proteins c-jun
  • Tamoxifen
  • Mitogen-Activated Protein Kinase 12