Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo

Yi Chen, Edwin A. Alvarez, Diana Azzam, Seth A. Wander, Natalia Guggisberg, Mercè Jordà, Zhenlin Ju, Bryan T. Hennessy, Joyce M. Slingerland

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Antiestrogen therapies arrest susceptible estrogen receptor (ER)-positive breast cancers by increasing p27. Since Src phosphorylates p27 to promote p27 proteolysis, Src activation observed in up to 40% of ER-positive cancers may contribute to antiestrogen resistance. In this article, we show that treatment with the Src-inhibitor saracatinib (AZD0530) together with ER-blocking drugs increased breast cancer cell cycle arrest via p27. Saracatinib and fulvestrant together more effectively increased p27, reduced Ki67, and impaired MDA-MB-361 xenograft tumor growth in vivo than either of the drugs alone. In contrast, saracatinib monotherapy rapidly gave rise to drug resistance. Since combined ER and Src inhibition delays development of resistance in vivo, these data support further clinical investigation of saracatinib in combination with fulvestrant for women with ER-positive breast cancer. Proteomic analysis revealed striking bypass activation of the mTOR pathway in saracatinib-resistant tumors. mTORC1 activation also arose following long-term culture of ER-positive breast cancer lines in the presence of saracatinib. These data indicate the utility of proteomic analysis of drug-resistant tumors to identify potential means of drug resistance. The use of mTOR kinase inhibitors with saracatinib may subvert drug resistance and prove to be more effective than saracatinib alone.

Original languageEnglish (US)
Pages (from-to)69-78
Number of pages10
JournalBreast cancer research and treatment
Volume128
Issue number1
DOIs
StatePublished - Jul 1 2011

Keywords

  • Breast cancer
  • Cell cycle
  • Fulvestrant
  • p27
  • Src inhibitor
  • Tamoxifen

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo'. Together they form a unique fingerprint.

  • Cite this