dc.contributor.author
Sonnenblick, Amir
dc.contributor.author
Brohée, Sylvain
dc.contributor.author
Fumagalli, Debora
dc.contributor.author
Vincent, Delphine
dc.contributor.author
Venet, David
dc.contributor.author
Ignatiadis, Michail
dc.contributor.author
Salgado, Roberto
dc.contributor.author
Eynden, Gert Van den
dc.contributor.author
Rothé, Françoise
dc.contributor.author
Desmedt, Christine
dc.contributor.author
Neven, Patrick
dc.contributor.author
Loibl, Sibylle
dc.contributor.author
Denkert, Carsten
dc.contributor.author
Joensuu, Heikki
dc.contributor.author
Loi, Sherene
dc.contributor.author
Sirtaine, Nicolas
dc.contributor.author
Kellokumpu-Lehtinen, Pirkko-Liisa
dc.contributor.author
Piccart, Martine
dc.contributor.author
Sotiriou, Christos
dc.date.accessioned
2018-06-08T03:22:17Z
dc.date.available
2015-08-31T07:41:16.387Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/15033
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-19221
dc.description.abstract
Background The likelihood of recurrence in patients with breast cancer who
have HER2-positive tumors is relatively high, although trastuzumab is a
remarkably effective drug in this setting. Signal transducer and activator of
transcription 3 protein (STAT3), a transcription factor that is persistently
tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic
signaling pathways, activates downstream proliferative and anti-apoptotic
pathways. We hypothesized that pSTAT3 expression in HER2-positive breast
cancer will confer trastuzumab resistance. Methods We integrated reverse phase
protein array (RPPA) and gene expression data from patients with HER2-positive
breast cancer treated with trastuzumab in the adjuvant setting. Results We
show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict
pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This
suggests that STAT3 induces a characteristic set of gene expression changes in
HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated
with trastuzumab resistance (log rank P = 0.049). These results were confirmed
using data from the prospective, randomized controlled FinHer study, where the
effect was especially prominent in HER2-positive estrogen receptor
(ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively
activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and
stromal reactivation. Conclusions This study provides compelling evidence for
a link between pSTAT3 and trastuzumab resistance in HER2-positive primary
breast cancers. Our results suggest that it may be valuable to add agents
targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive
breast cancer.
de
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
Phosphorylated STAT3
dc.subject
Randomised trial
dc.subject
Trastuzumab resistance
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit
dc.title
Constitutive phosphorylated STAT3-associated gene signature is predictive for
trastuzumab resistance in primary HER2-positive breast cancer
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation
BMC Medicine. - 13 (2015), Artikel Nr. 177
dcterms.bibliographicCitation.doi
10.1186/s12916-015-0416-2
dcterms.bibliographicCitation.url
http://www.biomedcentral.com/1741-7015/13/177
refubium.affiliation
Charité - Universitätsmedizin Berlin
de
refubium.mycore.fudocsId
FUDOCS_document_000000023001
refubium.note.author
Der Artikel wurde in einer Open-Access-Zeitschrift publiziert.
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000005328
dcterms.accessRights.openaire
open access