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dc.contributor.authorSonnenblick, A
dc.contributor.authorBrohee, S
dc.contributor.authorFumagalli, D
dc.contributor.authorVincent, D
dc.contributor.authorVenet, D
dc.contributor.authorIgnatiadis, M
dc.contributor.authorSalgado, R
dc.contributor.authorVan den Eynden, G
dc.contributor.authorRothe, F
dc.contributor.authorDesmedt, C
dc.contributor.authorNeven, P
dc.contributor.authorLoibl, S
dc.contributor.authorDenkert, C
dc.contributor.authorJoensuu, H
dc.contributor.authorLoi, S
dc.contributor.authorSirtaine, N
dc.contributor.authorKellokumpu-Lehtinen, P-L
dc.contributor.authorPiccart, M
dc.contributor.authorSotiriou, C
dc.date.accessioned2021-02-04T01:31:20Z
dc.date.available2021-02-04T01:31:20Z
dc.date.issued2015-08-03
dc.identifierpii: 10.1186/s12916-015-0416-2
dc.identifier.citationSonnenblick, A., Brohee, S., Fumagalli, D., Vincent, D., Venet, D., Ignatiadis, M., Salgado, R., Van den Eynden, G., Rothe, F., Desmedt, C., Neven, P., Loibl, S., Denkert, C., Joensuu, H., Loi, S., Sirtaine, N., Kellokumpu-Lehtinen, P. -L., Piccart, M. & Sotiriou, C. (2015). Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer. BMC MEDICINE, 13 (1), https://doi.org/10.1186/s12916-015-0416-2.
dc.identifier.issn1741-7015
dc.identifier.urihttp://hdl.handle.net/11343/259390
dc.description.abstractBACKGROUND: 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.
dc.languageEnglish
dc.publisherBIOMED CENTRAL LTD
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleConstitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer
dc.typeJournal Article
dc.identifier.doi10.1186/s12916-015-0416-2
melbourne.affiliation.departmentSir Peter MacCallum Department of Oncology
melbourne.affiliation.facultyMedicine, Dentistry & Health Sciences
melbourne.source.titleBMC Medicine
melbourne.source.volume13
melbourne.source.issue1
dc.rights.licenseCC BY
melbourne.elementsid1070714
melbourne.contributor.authorLoi, Sherene
dc.identifier.eissn1741-7015
melbourne.accessrightsOpen Access


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