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Proteasome inhibitors prevent bi-directional HER2/estrogen-receptor cross-talk leading to cell death in endocrine and lapatinib-resistant HER2+/ER+ breast cancer cells

Thaler, Sonja; Schmidt, Marcus; Roßwag, Sven; Thiede, Gitta; Schad, Arno; Sleeman, Jonathan P. ORCID iD icon 1
1 Karlsruher Institut für Technologie (KIT)


Amplification and/or overexpression of the human epidermal growth factor 2 (HER2) oncogene occurs in about 13–15% of invasive breast cancer and triggers breast cancer cell proliferation, survival and metastatic progression. Around half of all breast cancers with HER2 overexpression co-express hormone receptors (HR) such as those for estrogen and progesterone. Aberrant signaling through HER2 and other members of the HER-family mediates endocrine-resistance in estrogen receptor alpha (ERα) positive breast cancer. On the other hand, ERα co-expression has been shown to attenuate the efficiency of anti-HER2 therapies. These findings indicate that HER2 and ERα synergize to escape from both anti-ERα and anti-HER2-targeted therapies. Rationally designed clinical trials that combine endocrine therapy with anti-HER2 agents to interfere with HER2/ERα cross-talk have been conducted. However, the outcome of these trials suggests that novel therapeutic approaches are needed to further improve inhibition of HER2 and other HER-family members in conjunction with a more efficient ERα blockade. Here, we demonstrate that carfilzomib and bortezomib stabilize the HER2-specific protein tyrosine phosphatase BDP1 leading to decreased HER2 autophosphorylation, reduced HER2 activity and subsequently attenuated activation of the PI3K/Akt-pathway, together with blockade of ERα expression. ... mehr

Volltext §
DOI: 10.5445/IR/1000075726
DOI: 10.18632/oncotarget.20261
Web of Science
Zitationen: 9
Zitationen: 10
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Toxikologie und Genetik (ITG)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2017
Sprache Englisch
Identifikator ISSN: 1949-2553
KITopen-ID: 1000075726
HGF-Programm 47.01.01 (POF III, LK 01) Biol.Netzwerke u.Synth.Regulat. ITG+ITC
Erschienen in OncoTarget
Verlag Impact Journals
Band 8
Heft 42
Seiten 72281-72301
Vorab online veröffentlicht am 14.08.2017
Nachgewiesen in Web of Science
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