caa a22 4500 606234616 CHVBK 20210128101238.0 cr unu---uuuuu 210128e20150701xx s 000 0 eng 10.1007/s11010-015-2409-z doi (NATIONALLICENCE)springer-10.1007/s11010-015-2409-z The ErbB3-binding protein EBP1 modulates lapatinib sensitivity in prostate cancer cells [Elektronische Daten] [Smita Awasthi, Heather Ezelle, Bret Hassel, Anne Hamburger] Although ErbB receptors have been implicated in prostate cancer progression, ErbB-directed drugs have not proven effective for prostate cancer treatment. The ErbB3-binding protein EBP1 affects both ErbB2 and androgen receptor signaling, two components of the response to ErbB-targeted therapies. We therefore examined the effects of EBP1 expression on the response to the ErbB1/2 tyrosine kinase inhibitor lapatinib. We found a negative correlation between endogenous EBP1 levels and lapatinib sensitivity in prostate cancer cell lines. We then overexpressed or inhibited expression of EBP1. Silencing EBP1 expression increased lapatinib sensitivity and overexpression of EBP1 increased resistance in androgen-containing media. Androgen depletion resulted in an increased sensitivity of androgen-dependent EBP1 expressing cells to lapatinib, but did not affect the lapatinib sensitivity of hormone resistant cells. However, EBP1 silenced cells were still more sensitive to lapatinib than EBP1-expressing cells in the absence of androgens. The increase in sensitivity to lapatinib following EBP1 silencing was associated with increased ErbB2 levels. In addition, lapatinib treatment increased ErbB2 levels in sensitive cells that express low levels of EBP1, but decreased ErbB2 levels in resistant EBP1-expressing cells. In contrast, ErbB3 and phospho ErbB3 levels were not affected by either changes in EBP1 levels or lapatinib treatment. The production of the ErbB3/4 ligand heregulin was increased in EBP1-silenced cells. EBP1-induced changes in AR levels were not associated with changes in lapatinib sensitivity. These studies suggest that the ability of EBP1 to activate ErbB2 signaling pathways results in increased lapatinib sensitivity. Springer Science+Business Media New York, 2015 EBP1 nationallicence Prostate cancer nationallicence ErbB2 nationallicence Lapatinib nationallicence Awasthi Smita Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, 21201, Baltimore, MD, USA aut Ezelle Heather Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, 21201, Baltimore, MD, USA aut Hassel Bret Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, 21201, Baltimore, MD, USA aut Hamburger Anne Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, 21201, Baltimore, MD, USA aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 405/1-2(2015-07-01), 177-186 0300-8177 405:1-2<177 2015 405 11010 https://doi.org/10.1007/s11010-015-2409-z text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-015-2409-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Awasthi Smita Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, 21201, Baltimore, MD, USA aut NATIONALLICENCE 700 1- Ezelle Heather Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, 21201, Baltimore, MD, USA aut NATIONALLICENCE 700 1- Hassel Bret Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, 21201, Baltimore, MD, USA aut NATIONALLICENCE 700 1- Hamburger Anne Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, 21201, Baltimore, MD, USA aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 405/1-2(2015-07-01), 177-186 0300-8177 405:1-2<177 2015 405 11010