Phosphoproteomic analysis identifies focal adhesion kinase 2 (FAK2) as a potential therapeutic target for tamoxifen resistance in breast cancer

Xinyan Wu, Muhammad Saddiq Zahari, Santosh Renuse, Raja Sekhar Nirujogi, Min Sik Kim, Srikanth S. Manda, Vered Stearns, Edward Gabrielson, Saraswati Sukumar, Akhilesh Pandey

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Tamoxifen, an estrogen receptor-α (ER) antagonist, is an important agent for the treatment of breast cancer. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying this resistance, we treated the MCF7 breast cancer cell line with tamoxifen for over six months and showed that this cell line acquired resistance to tamoxifen in vitro and in vivo. We performed SILAC-based quantitative phosphoproteomic profiling on the tamoxifen resistant and vehicle-treated sensitive cell lines to quantify the phosphorylation alterations associated with tamoxifen resistance. From >5600 unique phosphopeptides identified, 1529 peptides exhibited hyperphosphorylation and 409 peptides showed hypophosphorylation in the tamoxifen resistant cells. Gene set enrichment analysis revealed that focal adhesion pathway was one of the most enriched signaling pathways activated in tamoxifen resistant cells. Significantly, we showed that the focal adhesion kinase FAK2 was not only hyperphosphorylated but also transcriptionally upregulated in tamoxifen resistant cells. FAK2 suppression by specific siRNA knockdown or a small molecule inhibitor repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 is significantly associated with shorter metastasis-free survival in estrogen receptor-positive breast cancer patients treated with tamoxifen. Our studies suggest that FAK2 is a potential therapeutic target for the management of hormonerefractory breast cancers.

Original languageEnglish (US)
Pages (from-to)2887-2900
Number of pages14
JournalMolecular and Cellular Proteomics
Volume14
Issue number11
DOIs
StatePublished - Nov 2015

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology

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