NDLI: Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer

Content Provider	Springer Nature : BioMed Central
Author	Sonnenblick, Amir Brohée, Sylvain Fumagalli, Debora Vincent, Delphine Venet, David Ignatiadis, Michail Salgado, Roberto Van den Eynden, Gert Rothé, Françoise Desmedt, Christine Neven, Patrick Loibl, Sibylle Denkert, Carsten Joensuu, Heikki Loi, Sherene Sirtaine, Nicolas Kellokumpu-Lehtinen, Pirkko-Liisa Piccart, Martine Sotiriou, Christos
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.
Related Links	https://bmcmedicine.biomedcentral.com/counter/pdf/10.1186/s12916-015-0416-2.pdf
Ending Page	10
Page Count	10
Starting Page	1
File Format	HTM / HTML
ISSN	17417015
DOI	10.1186/s12916-015-0416-2
Journal	BMC Medicine
Issue Number	1
Volume Number	13
Language	English
Publisher	BioMed Central
Publisher Date	2015-08-03
Access Restriction	Open
Subject Keyword	Medicine Public Health Biomedicine Breast cancer FinHer HER2 Phosphorylated STAT3 Randomised trial Trastuzumab resistance Medicine/Public Health
Content Type	Text
Resource Type	Article
Subject	Medicine
Journal Impact Factor	7.1/2023
5-Year Journal Impact Factor	8.8/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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