Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer
AuthorSonnenblick, A; Brohee, S; Fumagalli, D; Vincent, D; Venet, D; Ignatiadis, M; Salgado, R; Van den Eynden, G; Rothe, F; Desmedt, C; ...
Source TitleBMC Medicine
PublisherBIOMED CENTRAL LTD
University of Melbourne Author/sLoi, Sherene
AffiliationSir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsSonnenblick, 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.
Access StatusOpen Access
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.
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