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

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    73 Scopus citations

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

    ASJC Scopus subject areas

    • Medicine(all)

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    Chu, I., Arnaout, A., Loiseau, S., Sun, J., Seth, A., McMahon, C., Chun, K., Hennessy, B., Mills, G. B., Nawaz, Z., & Slingerland, J. M. (2007). Src promotes estrogen-dependent estrogen receptor α proteolysis in human breast cancer. Journal of Clinical Investigation, 117(8), 2205-2215. https://doi.org/10.1172/JCI21739