Tumor STAT3 tyrosine phosphorylation status, as a predictor of benefit from adjuvant chemotherapy for breast cancer

Sonnenblick, Amir; Uziely, Beatrice; Nechushtan, Hovav; Kadouri, Luna; Galun, Eithan; Axelrod, Jonathan H.; Katz, Daniela; Daum, Hagit; Hamburger, Tamar; Maly, Bela; Allweis, Tanir; Peretz, Tamar

doi:10.1007/s10549-013-2453-x

Cited by 31 publications

(34 citation statements)

References 25 publications

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“…Deregulation of this pathway has been previously implicated in the promotion of oncogenic phenotypes, including tumorigenesis, invasion, metastasis, proliferation, survival, angiogenesis, anti-apoptosis and immune evasion 7,8 . In breast cancer, the JAK-STAT pathway has been shown to be altered by the following mechanisms: 1) downregulation of phosphotyrosine specific phosphatases 9–11 , 2) elevation of the JAK/STAT-activating ligand IL-6 12–14 , 3) activation of other upstream oncogenic pathways, such as ErbB1, c-Src 15 or PI3K/mTOR 16 , and 4) down-regulation of STAT3 negative regulators such as suppressor of cytokine signaling-3 (SOCS3) 17 .…”

Section: Introductionmentioning

confidence: 99%

Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence

et al. 2016

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Amplifications at 9p24 have been identified in breast cancer and other malignancies, but the genes within this locus casually associated with oncogenicity or tumor progression remain unclear. Targeted next-generation sequencing of post-chemotherapy triple-negative breast cancers (TNBC) identified a group of 9p24-amplified tumors, which contained focal amplification of the Janus kinase-2 (JAK2) gene. These patients had markedly inferior recurrence-free and overall survival compared to patients with TNBC without JAK2 amplification. Presence of JAK2/9p24 amplifications occurred at higher rates in chemotherapy-treated TNBCs than in untreated TNBCs or basal-like breast cancers, or in other subtypes. Similar rates of JAK2 amplification were confirmed in patient-derived TNBC xenografts. In patients where longitudinal specimens were available, JAK2 amplification was selected for during neoadjuvant chemotherapy and eventual metastatic spread, suggesting a role in tumorigenicity and chemoresistance, phenotypes often attributed to a cancer stem-like cell population. In TNBC cell lines with JAK2 copy gains or amplification, specific inhibition of JAK2-STAT6 signaling reduced mammosphere formation and cooperated with chemotherapy in reducing tumor growth in vivo. In these cells, inhibition of JAK1-STAT3 signaling had little effect or, in some cases, counteracted JAK2-specific inhibition. Collectively, these results suggest that JAK2-specific inhibitors are more efficacious than dual JAK1/2 inhibitors against JAK2-amplified TNBCs. Furthermore, JAK2 amplification is a potential biomarker for JAK2-dependence which, in turn, can be used to select patients for clinical trials with JAK2 inhibitors.

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Section: Introductionmentioning

confidence: 99%

Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence

et al. 2016

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“…This may not be surprising, given the universe presence of constitutive activation of STAT3 signaling in these cancer cells and their well-characterized prosurvival effect. This novel combination strategy warrants further clinical investigation in patients with trastuzumab-resistant tumors given that constitutively activated STAT3 is present in a quite fraction of patients with HER2-positive breast and gastric cancer [38, 39]. …”

Section: Discussionmentioning

confidence: 99%

Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression

Zhao

et al. 2014

Oncotarget

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Although HER2-targeting antibody trastuzumab confers a substantial benefit for patients with HER2-overexpressing breast and gastric cancer, overcoming trastuzumab resistance remains a large unmet need. In this study, we revealed a STAT3-centered positive feedback loop that mediates the resistance of trastuzumab. Mechanistically, chronic exposure of trastuzumab causes the upregulation of fibronection (FN), EGF and IL-6 in parental trastuzumab-sensitive breast and gastric cells and convergently leads to STAT3 hyperactivation. Activated STAT3 enhances the expression of FN, EGF and IL-6, thus constituting a positive feedback loop which amplifies and maintains the STAT3 signal; furthermore, hyperactivated STAT3 signal promotes the expression of MUC1 and MUC4, consequently mediating trastuzumab resistance via maintenance of persistent HER2 activation and masking of trastuzumab binding to HER2 respectively. Genetic or pharmacological inhibition of STAT3 disrupted STAT3-dependent positive feedback loop and recovered the trastuzumab sensitivity partially due to increased apoptosis induction. Combined trastuzumab with STAT3 inhibition synergistically suppressed the growth of the trastuzumab-resistant tumor xenografts in vivo. Taken together, our results suggest that feedback activation of STAT3 constitutes a key node mediating trastuzumab resistance. Combinatorial targeting on both HER2 and STAT3 may enhance the efficacy of trastuzumab or other HER2-targeting agents in HER2-positive breast and gastric cancer.

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“…Intriguingly, it has also been reported that high nuclear expression of Tyr705-phosphorylated STAT3 is correlated with improved survival, smaller tumors, or less aggressive histology in various tumors, including breast cancer [73,74], head and neck cancer [75], lung cancer [76], gastric cancer [77], soft tissue leiomyosarcoma [78], and advanced rectal cancer [79]. However, in pancreatic ductal adenocarcinoma, no association was seen between STAT3 phosphorylation and patient survival [80].…”

Section: Jak/stat Signaling In Different Cancer Typesmentioning

confidence: 99%

The Role of STAT3 in Thyroid Cancer

Sosonkina

Starenki

Park

2014

Cancers

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Thyroid cancer is the most common endocrine malignancy and its global incidence rates are rapidly increasing. Although the mortality of thyroid cancer is relatively low, its rate of recurrence or persistence is relatively high, contributing to incurability and morbidity of the disease. Thyroid cancer is mainly treated by surgery and radioiodine remnant ablation, which is effective only for non-metastasized primary tumors. Therefore, better understanding of the molecular targets available in this tumor is necessary. Similarly to many other tumor types, oncogenic molecular alterations in thyroid epithelium include aberrant signal transduction of the mitogen-activated protein kinase, phosphatidylinositol 3-kinase/AKT (also known as protein kinase B), NF-кB, and WNT/β-catenin pathways. However, the role of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT3) pathway, a well-known mediator of tumorigenesis in different tumor types, is relatively less understood in thyroid cancer. Intriguingly, recent studies have demonstrated that, in thyroid cancer, the JAK/STAT3 pathway may function in the context of tumor suppression rather than promoting tumorigenesis. In this review, we provide an update of STAT3 function in thyroid cancer and discuss some of the evidences that support this hypothesis.

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Tumor STAT3 tyrosine phosphorylation status, as a predictor of benefit from adjuvant chemotherapy for breast cancer

Cited by 31 publications

References 25 publications

Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence

Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence

Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression

The Role of STAT3 in Thyroid Cancer

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