The prognostic significance of STAT3 in invasive breast cancer: analysis of protein and mRNA expressions in large cohorts

Abstract

Signal transducer and activator of transcription (STAT) transcription factors family are involved in diverse cellular biological functions. Reports regarding the prognostic impact of STAT3 expression in breast cancer (BC) are variable whether being a factor of poor or good prognosis. Immunohistochemical expression of phospho-STAT3 (pSTAT3) was studied in large series of invasive BC (n = 1270). pSTAT3 and STAT3 were quantified using reverse phase protein array (RPPA) on proteins extracted from macro-dissected FFPE tissues (n = 49 cases). STAT3 gene expression in the METABRIC cohort was also investigated. STAT3 gene expression prognostic impact was externally validated using the online BC gene expression data (n = 26 datasets, 4.177 patients). pSTAT3 was expressed in the nuclei and cytoplasm of invasive BC cells. Nuclear pSTAT3 overexpression was positively associated with smaller tumour size, lower grade, good NPI, negative lymphovascular invasion (LVI), ER+, PgR+, p53-, HER2-, and low Ki67LI and an improved breast cancer-specific survival (BCSS), independently of other factors. On RPPA, the mean pSTAT3 and STAT3 expressions were higher in ER+, PgR+, and smaller size tumours. Higher STAT3 transcripts in the METABRIC cohort were observed in cases with favourable prognostic criteria and as well as improved BCSS within the whole cohort, ER+ cohort with and without hormonal therapy, and ER- cohort including those who did not receive adjuvant chemotherapy. Pooled STAT3 gene expression data in the external validation cohort showed an association with improved patients' outcome (P < 0.001, HR = 0.84, 95 % CI 0.79-0.90). Results of this study suggest nuclear localisation of pSTAT3 as favourable prognostic marker in invasive BC, results re-enforced by analysis of STAT3 gene expression data. This good prognostic advantage was maintained in patients who received and who did not receive adjuvant therapy. Therefore, STAT3 could have context-dependent molecular roles of in BC, results which warrant further prospective verification in clinical trials.

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 IHC staining of total and ph-STAT1 and STAT3 was homogenous in both the cytoplasm and nuclei of tumour cells, which is consistent with previous reports [22]. The staining was also observed in the surrounding stromal cells (fibroblasts and infiltrating inflammatory cells) with variable degrees of positivity.…”

“…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).…”

The prognostic values of signal transducers activators of transcription family in ovarian cancer

“…STAT3, which can be triggered by cytokines and growth factors [31,32], was constitutively activated in some types of cancer [10,15,16]. It was not only involved in cancer development and progression but also contributed to their survival.…”

“…Grabner et al [33] detected STAT3 may act as a tumor suppressor through STAT3-NF-κB-IL-8 axis in KRAS mutant lung adenocarcinoma and a molecular marker with favorable prognostic value. In the same line of evidence, it was shown that p-STAT3 was reported as a favorable prognosis marker in breast cancer [15], head and neck squamous cell carcinoma [16], and leiomyosarcoma [34]. Amongst the STAT family, STAT3 is the most studied STAT in ovarian cancer.…”

Approaching non-canonical STAT3 signaling to redefine cancer therapeutic strategy

“…The overexpression of nuclear localized pY705 STAT3 showed a positive correlation with various clinicopathological parameters like small tumor size, lower grade tumor, negative lymphovascular invasion, hormone receptor positive subtypes and low Ki67 proliferation marker as well as improved breast cancer specific survival (BCSS). While higher STAT3 transcript levels in the METABRIC cohort was observed in the cases with improved BCSS and good prognostic markers, indicating high levels of nuclear pY705 Stat3 as a good prognostic criteria for breast cancer [51]. In another study tissue microarray based analysis of STAT3 and pY705 STAT3 was done in a cohort of 346 node negative breast cancer cases.…”