Cross talk between ERα and Src signaling and its relevance to ER status and hormone responsiveness

Jun Sun, Wen Zhou, Zafar Nawaz, Joyce M Slingerland

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

While two thirds of breast cancers are ER positive and a majority of these are responsive to endocrine therapies, up to one third of newly diagnosed breast cancers lack detectable ER protein. ER negative breast cancers are thought to be resistance to endocrine therapy. Here we review several potential mechanisms underlying the ER negative status of these breast cancers. The role of cross-talk between ER and Src-activated signal transduction as a mediator of both ER proteolysis and ER transactivation is discussed. Src kinase is often activated in breast cancer. Liganded ER rapidly and transiently activates Src which phosphorylates ER. For a subset of ER-responsive promoters, ER phosphorylation by Src leads to enhanced ER binding to the promoter, increased interactions with E3 ubiquitin ligases, and rapid ER degradation, in a process in which ER activation is coupled to its degradation. Thus, the function of ER may not be solely dependent on the steady state levels of ER protein. A subset of ER negative breast cancers that have ER mRNA but lack detectable ER protein levels may ultimately prove to be responsive to estrogen. These observations may have broader implications for estrogen driven gene expression. Cells of estrogen responsive tissues (ovary, bone, brain and intestine) could have low ER protein levels, but retain responses to estrogen through estrogen driven ER proteolysis-coupled transcriptional activity.

Original languageEnglish (US)
Title of host publicationAdvances in Rapid Sex-Steroid Action: New Challenges and New Chances in Breast and Prostate Cancers
PublisherSpringer New York
Pages61-78
Number of pages18
Volume9781461417644
ISBN (Print)9781461417644, 1461417635, 9781461417637
DOIs
StatePublished - Aug 1 2012

Keywords

  • Breast cancer
  • Estrogen receptor
  • Proteolysis
  • Signal transduction
  • Src kinase
  • Ubiquitin

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Sun, J., Zhou, W., Nawaz, Z., & Slingerland, J. M. (2012). Cross talk between ERα and Src signaling and its relevance to ER status and hormone responsiveness. In Advances in Rapid Sex-Steroid Action: New Challenges and New Chances in Breast and Prostate Cancers (Vol. 9781461417644, pp. 61-78). Springer New York. https://doi.org/10.1007/978-1-4614-1764-4_4