Tissue microarray-based study of patients with lymph node-positive breast cancer shows tyrosine phosphorylation of signal transducer and activator of transcription 3 (tyrosine705-STAT3) is a marker of good prognosis

Sonnenblick, Amir; Shriki, Anat; Galun, Eithan; Axelrod, Jonathan H.; Daum, Hagit; Rottenberg, Yakir; Hamburger, Tamar; Mali, Bela; Peretz, Tamar

doi:10.1007/s12094-012-0789-z

Cited by 40 publications

(31 citation statements)

References 19 publications

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“…High total STAT3 was significantly associated with improved outcome in three studies [16, 18, 19], and with poor outcome in one study [20]. Ph-STAT3 expression was not associated with breast cancer survival in two studies [13, 21], and was associated with improved survival in large cohort of patients [22], patients with lymph node positive tumours [23], and patients treated with adjuvant chemotherapy [24]. In contrast, ph-STAT3 was a significant predictor of worse survival in one study [17] (Table 1).…”

Section: Introductionmentioning

confidence: 99%

The relationship between total and phosphorylated STAT1 and STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer

2016

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The aim of the present study was to examine the relationship between tumour cell expression of total and phosphorylated STAT1 (ph-STAT1) and STAT3 (ph-STAT-3), components of tumour microenvironment and survival in patients with invasive ductal breast cancer.Immunohistochemical analysis of total and ph-STAT1, and STAT3 were performed on tissue microarray of 384 breast cancer specimens. Tumour cell expression of STAT1 and STAT3 at both cytoplasmic and nuclear locations were combined and identified as STAT1/STAT3 tumour cell expression. These results were related to cancer specific survival (CSS) and phenotypic features of the tumour and the host.High ph-STAT1 and ph-STAT3 tumour cell expression were associated with increased ER (both P≤0.001) and PR (both P <0.05), reduced tumour grade (P=0.015 and P<0.001 respectively) and necrosis (both P=0.001). Ph-STAT1 was associated with increased general inflammatory infiltrate (P=0.007) and ph-STAT3 was associated with lower CD4+ infiltration (P=0.024). In multivariate survival analysis, only high ph-STAT3 tumour cell expression was a predictor of improved CSS (P=0.010) independent of other tumour and host-based factors.STAT1 and STAT3 tumour cell expression appeared to be an important determinant of favourable outcome in patients with invasive ductal breast cancer. The present results suggest that STAT1 and STAT3 may affect disease outcome through direct impact on tumour cells, counteracting aggressive tumour features, as well as interaction with the surrounding microenvironment.

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Section: Introductionmentioning

confidence: 99%

The relationship between total and phosphorylated STAT1 and STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer

2016

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“…The study of phosphorylation in signal transduction events is especially important in pathways that are known to be dysregulated in disease states. Recent studies have defined a role for measuring the kinetics of phosphorylation events in not only the diagnosis/prognosis of diseases (Mackenzie et al, 2012; Sonnenblick et al, 2012; Woost et al, 2011), but also the efficacy of therapies, such as with the bcr/abl kinase inhibitor Imatinib, directed towards epigenetic alterations. (Druker et al, 2001; Hedley et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Simultaneous assessment of NF-κB/p65 phosphorylation and nuclear localization using imaging flow cytometry

Maguire

O’Loughlin

Minderman

2015

Journal of Immunological Methods

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Aberrant activity of Nuclear Factor–kappaB (NF-κB) is associated with many diseases and is therapeutically targeted. Post-translational modifications, particularly phosphorylation of the RELA/p65 sub-unit, are essential for cytoplasmic to nuclear localization of NF-κB/p65 and initiation of transcription of downstream target genes. Immunoblot and phospho-flow cytometry has been used to study the relationship between phosphorylation motifs and NF-κB activation and microscopic analysis of nuclear localization of p65 is also used as a parameter for activation. The labor intensive nature of these approaches commonly limits the number of sampling points or replicates. Recent insights in the relationship between p65 phosphorylation motifs and its nuclear localization indicate that these parameters have different significance and should not be used interchangeably. In this study, we demonstrate feasibility and reproducibility of studying the relationship between p65 phosphorylation and nuclear translocation using imaging flow cytometry (IFC). TNFα- or PMA/Ionomycin-induced phosphorylation of p65 at serine 529 in cell line models and healthy donor lymphocytes served as the experimental model. IFC analysis demonstrated that expression of phosphorylated serine 529 (P-p65s529) increased rapidly following stimulation and that nuclear localization of P-p65s529 followed the nuclear localization pattern of total p65. However, in the presence of tacrolimus, P-p65s529 expression was inhibited without affecting nuclear localization of total p65. The data demonstrate the application of IFC to simultaneously assess phosphorylation of p65 and its cellular localization and the results obtained by this analysis corroborate current insights regarding the specific effect of tacrolimus on serine 529 phosphorylation.

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“…Subsequently, a number of well-performed studies have suggested that the activation of STAT3 might not be uniformly associated with increased malignancy, and that in some circumstances STAT3 might act as a functional tumor suppressor or its activation may be associated with an improved prognosis [7,8,9,10]. Thus, dissecting these dichotomous roles is an important question in cancer biology.…”

Section: Introductionmentioning

confidence: 99%

STAT3 Activity and Function in Cancer: Modulation by STAT5 and miR-146b

Walker

Xiang

Frank

2014

Cancers

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The transcription factor STAT3 regulates genes that control critical cellular processes such as proliferation, survival, pluripotency, and motility. Thus, under physiological conditions, the transcriptional function of STAT3 is tightly regulated as one part of a complex signaling matrix. When these processes are subverted through mutation or epigenetic events, STAT3 becomes highly active and drives elevated expression of genes underlying these phenotypes, leading to malignant cellular behavior. However, even in the presence of activated STAT3, other cellular modulators can have a major impact on the biological properties of a cancer cell, which is reflected in the clinical behavior of a tumor. Recent evidence has suggested that two such key modulators are the activation status of other STAT family members, particularly STAT5, and the expression of STAT3-regulated genes that are part of negative feedback circuits, including microRNAs such as miR-146b. With attention to these newly emerging areas, we will gain greater insight into the consequence of STAT3 activation in the biology of human cancers. In addition, understanding these subtleties of STAT3 signaling in cancer pathogenesis will allow the development of more rational molecular approaches to cancer therapy.

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Tissue microarray-based study of patients with lymph node-positive breast cancer shows tyrosine phosphorylation of signal transducer and activator of transcription 3 (tyrosine705-STAT3) is a marker of good prognosis

Abstract: These findings support the role of Phospho- STAT3 as an important independent prognostic marker in node-positive breast cancer patients.

Cited by 40 publications

References 19 publications

The relationship between total and phosphorylated STAT1 and STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer

The relationship between total and phosphorylated STAT1 and STAT3 tumour cell expression, components of tumour microenvironment and survival in patients with invasive ductal breast cancer

Simultaneous assessment of NF-κB/p65 phosphorylation and nuclear localization using imaging flow cytometry

STAT3 Activity and Function in Cancer: Modulation by STAT5 and miR-146b

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