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Ebp50: A Novel Biomarker for Resistance to Endocrine and HER‐2 Targeted Therapies in Breast Cancer
Author(s) -
gu Guowei,
Covington Kyle Richard,
Fernandez Natalie Michelle,
Andoˈ Sebastiano,
Fuqua Suzanne A.W.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.lb522
Subject(s) - gene knockdown , cancer research , trastuzumab , breast cancer , pi3k/akt/mtor pathway , biology , lapatinib , chemistry , signal transduction , medicine , microbiology and biotechnology , cancer , cell culture , genetics
Backgroud EBP50 functions as a molecular scaffold to coordinate ion transport and second messenger signal transduciton. Recently, a number of studies suggest a role for EBP50 expression in cancer progression. Methods Microarray profiling. Stable transfection. Soft agar and MTT growth assays. Immunoblot and immunoprecipitation assays. Confocal microscopy. Results The mean levels of EBP50 were reduced in the tamoxifen (Tam) ‐resistant, metastatic breast tumors compared to Tam‐sensitive tumors. Knockdown of EBP50 decreased Tam sensitivity in MCF‐7 and ZR75B cells. EBP50 knockdown cells showed higher levels of phosphorylated HER2 and EGFR, as well as their downstream signalling pathways. PI3K/AKT inhibitors were able to restore Tam sensitivity in knockdown cells. Similarly, knockdown EBP50 in ERα/HER2 positive BT‐474 cells increased costitutive pHER2 and these cells were resistant not only to Tam, but also to Trastuzumab (Tras) treatment. EGFR inhibitor or Lapatinib were able to restore Tras sensitivity. We demonstrate that EBP50 is capable of binding to HER2 using immunoprecipitation and confocal microscopes, suggesting that EBP50 interacts directly with HER2. Our data suggest that EBP50 is a novel negative regulator of HER2 signaling, and its loss conferred resistance to both Tam and Tras. We hypothesize that EBP50 levels might be a new predictive biomarker for targeted therapy.