Abstract
BackgroundThe 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.MethodsWe integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting.ResultsWe 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.ConclusionsThis 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0416-2) contains supplementary material, which is available to authorized users.
Highlights
The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, trastuzumab is a remarkably effective drug in this setting
Signal transducer and activator of transcription proteins (STATs) are latent cytoplasmic proteins that form functional dimers with each other when activated by tyrosine phosphorylation, upon which they translocate to the nucleus to regulate the expression of genes by binding to specific elements within gene promoters
Results phosphorylated STAT3 (pSTAT3) HER2-positive breast cancers are associated with a distinct gene expression profile reverse phase protein array (RPPA) of pSTAT3 was performed on 51 primary HER2-positive breast cancers using the Responsify dataset, which is composed of 108 HER2-positive early stage breast cancer patients treated with adjuvant trastuzumab (Additional file 1: Table S1A)
Summary
The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, 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. Trastuzumab is a remarkably effective therapy for patients with HER2-positive breast cancers, both in the metastatic and adjuvant settings [1,2,3]. Several potential mechanisms to Signal transducer and activator of transcription proteins (STATs) are latent cytoplasmic proteins that form functional dimers with each other when activated by tyrosine phosphorylation, upon which they translocate to the nucleus to regulate the expression of genes by binding to specific elements within gene promoters. STAT3 has been shown to play a role in the pathogenesis of breast cancer through its positive effects on invasion, stem cell expansion, and modulation of the environment [10]
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