Src Promotes Estrogen-Dependent Estrogen Receptor Alpha Proteolysis in Human Breast Cancer

J Clin Invest. 2007 Aug;117(8):2205-15. doi: 10.1172/JCI21739.

Abstract

Estrogen drives both transcriptional activation and proteolysis of estrogen receptor alpha (ER alpha; encoded by ESR1). Here we observed variable and overlapping ESR1 mRNA levels in 200 ER alpha-negative and 50 ER alpha-positive primary breast cancers examined, which suggests important posttranscriptional ER alpha regulation. Our results indicate that Src cooperates with estrogen to activate ER alpha proteolysis. Inducible Src stimulated ligand-activated ER alpha transcriptional activity and reduced ER alpha t(1/2). Src and ER alpha levels were inversely correlated in primary breast cancers. ER alpha-negative primary breast cancers and cell lines showed increased Src levels and/or activity compared with ER alpha-positive cancers and cells. ER alpha t(1/2) was reduced in ER alpha-negative cell lines. In both ER alpha-positive and -negative cell lines, both proteasome and Src inhibitors increased ER alpha levels. Src inhibition impaired ligand-activated ER alpha ubiquitylation and increased ER alpha levels. Src siRNA impaired ligand-activated ER alpha loss in BT-20 cells. Pretreatment with Src increased ER alpha ubiquitylation and degradation in vitro. These findings provide what we believe to be a novel link between Src activation and ER alpha proteolysis and support a model whereby crosstalk between liganded ER alpha and Src drives ER alpha transcriptional activity and targets ER alpha for ubiquitin-dependent proteolysis. Oncogenic Src activation may promote not only proliferation, but also estrogen-activated ER alpha loss in a subset of ER alpha-negative breast cancers, altering prognosis and response to therapy.

Publication types

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

MeSH terms

  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy
  • Cell Line, Tumor
  • Enzyme Activation / drug effects
  • Estrogen Receptor alpha / biosynthesis*
  • Estrogens / metabolism
  • Estrogens / pharmacology
  • Female
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • Neoplasm Proteins / biosynthesis*
  • Prognosis
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein Processing, Post-Translational* / drug effects
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • RNA, Small Interfering / pharmacology
  • Transcription, Genetic / drug effects
  • Ubiquitin / metabolism
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism*

Substances

  • Estrogen Receptor alpha
  • Estrogens
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • RNA, Neoplasm
  • RNA, Small Interfering
  • Ubiquitin
  • src-Family Kinases
  • Proteasome Endopeptidase Complex