Src promotes estrogen-dependent estrogen receptor α proteolysis in human breast cancer

Isabel Chu, Angel Arnaout, Sophie Loiseau, Jun Sun, Arun Seth, Chris McMahon, Kathy Chun, Bryan Hennessy, Gordon B. Mills, Zafar Nawaz, Joyce M Slingerland

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Estrogen drives both transcriptional activation and proteolysis of estrogen receptor α (ERα; encoded by ESR1). Here we observed variable and overlapping ESR1 mRNA levels in 200 ERα-negative and 50 ERα-positive primary breast cancers examined, which suggests important posttranscriptional ERα regulation. Our results indicate that Src cooperates with estrogen to activate ERα proteolysis. Inducible Src stimulated ligand-activated ERα transcriptional activity and reduced ERα t1/2. Src and ERα levels were inversely correlated in primary breast cancers. ERα-negative primary breast cancers and cell lines showed increased Src levels and/or activity compared with ERα-positive cancers and cells. ERα t1/2 was reduced in ERα-negative cell lines. In both ERα-positive and -negative cell lines, both proteasome and Src inhibitors increased ERα levels. Src inhibition impaired ligand-activated ERα ubiquitylation and increased ERα levels. Src siRNA impaired ligand-activated ERα loss in BT-20 cells. Pretreatment with Src increased ERα ubiquitylation and degradation in vitro. These findings provide what we believe to be a novel link between Src activation and ERα proteolysis and support a model whereby crosstalk between liganded ERα and Src drives ERα transcriptional activity and targets ERα for ubiquitin-dependent proteolysis. Oncogenic Src activation may promote not only proliferation, but also estrogen-activated ERα loss in a subset of ERα-negative breast cancers, altering prognosis and response to therapy.

Original languageEnglish
Pages (from-to)2205-2215
Number of pages11
JournalJournal of Clinical Investigation
Volume117
Issue number8
DOIs
StatePublished - Aug 1 2007

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Estrogen Receptors
Proteolysis
Estrogens
Breast Neoplasms
Ubiquitination
Ligands
Cell Line
Proteasome Inhibitors
Ubiquitin
Small Interfering RNA
Transcriptional Activation
Messenger RNA
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Src promotes estrogen-dependent estrogen receptor α proteolysis in human breast cancer. / Chu, Isabel; Arnaout, Angel; Loiseau, Sophie; Sun, Jun; Seth, Arun; McMahon, Chris; Chun, Kathy; Hennessy, Bryan; Mills, Gordon B.; Nawaz, Zafar; Slingerland, Joyce M.

In: Journal of Clinical Investigation, Vol. 117, No. 8, 01.08.2007, p. 2205-2215.

Research output: Contribution to journalArticle

Chu, I, Arnaout, A, Loiseau, S, Sun, J, Seth, A, McMahon, C, Chun, K, Hennessy, B, Mills, GB, Nawaz, Z & Slingerland, JM 2007, 'Src promotes estrogen-dependent estrogen receptor α proteolysis in human breast cancer', Journal of Clinical Investigation, vol. 117, no. 8, pp. 2205-2215. https://doi.org/10.1172/JCI21739
Chu, Isabel ; Arnaout, Angel ; Loiseau, Sophie ; Sun, Jun ; Seth, Arun ; McMahon, Chris ; Chun, Kathy ; Hennessy, Bryan ; Mills, Gordon B. ; Nawaz, Zafar ; Slingerland, Joyce M. / Src promotes estrogen-dependent estrogen receptor α proteolysis in human breast cancer. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 8. pp. 2205-2215.
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