Loss of Nuclear Localized and Tyrosine Phosphorylated Stat5 in Breast Cancer Predicts Poor Clinical Outcome and Increased Risk of Antiestrogen Therapy Failure

Abstract

A B S T R A C T PurposeTo investigate nuclear localized and tyrosine phosphorylated Stat5 (Nuc-pYStat5) as a marker of prognosis in node-negative breast cancer and as a predictor of response to antiestrogen therapy. Patients and MethodsLevels of Nuc-pYStat5 were analyzed in five archival cohorts of breast cancer by traditional diaminobenzidine-chromogen immunostaining and pathologist scoring of whole tissue sections or by immunofluorescence and automated quantitative analysis (AQUA) of tissue microarrays. ResultsNuc-pYStat5 was an independent prognostic marker as measured by cancer-specific survival (CSS) in patients with node-negative breast cancer who did not receive systemic adjuvant therapy, when adjusted for common pathology parameters in multivariate analyses both by standard chromogen detection with pathologist scoring of whole tissue sections (cohort I; n ϭ 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n ϭ 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n ϭ 180) revealed frequent loss of Nuc-pYStat5 in invasive carcinoma compared to normal breast epithelia or ductal carcinoma in situ, and general loss of Nuc-pYStat5 in lymph node metastases. In cohort IV (n ϭ 221), loss of Nuc-pYStat5 was associated with increased risk of antiestrogen therapy failure as measured by univariate CSS and time to recurrence (TTR). More sensitive AQUA quantification of Nuc-pYStat5 in antiestrogen-treated patients (cohort V; n ϭ 97) identified by multivariate analysis patients with low Nuc-pYStat5 at elevated risk for therapy failure (CSS hazard ratio [HR], 21.55; 95% CI, 5.61 to 82.77; P Ͻ .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P ϭ .001). ConclusionNuc-pYStat5 is an independent prognostic marker in node-negative breast cancer. If confirmed in prospective studies, Nuc-pYStat5 may become a useful predictive marker of response to adjuvant hormone therapy.

STAT5 in Cancer and Immunity

“…Activated STAT5 was associated with a favorable prognosis in breast cancer patients [150]. Peck et al showed that a loss of pSTAT5 from the nucleus predicts for a poor clinical outcome along with the possibility of failure to respond to endocrine therapy in ER+ve breast cancer patients [151]. Interestingly, the expression of Bcl6 is inhibited by prolactin mediated activation of STAT5 in breast cancer [152].…”

Zinc Finger Homeodomain Factor Zfhx3 Is Essential for Mammary Lactogenic Differentiation by Maintaining Prolactin Signaling Activity

“…The decrease of phosphorylated STAT5 is correlated with poorer patient survival and predicts both poor clinical outcome and increased risk of antiestrogen therapy failure (61)(62)(63)(64)(65). PRLR has been shown to suppress epithelial-mesenchymal transition and invasiveness of breast cancer cells (66), and PRLR expression is significantly down-regulated in invasive breast cancer, the down-regulation being associated with lymph node metastasis, lower tumor grade, and metastasis-free survival in breast cancer patients (67).…”

STAT5a-targeting miRNA enhances chemosensitivity to cisplatin and 5-fluorouracil in human colorectal cancer cells

“…As STAT3 has been the focus of cancer research, STAT3 inhibitors are being investigated, and a growing number of preclinical studies are ongoing. Therefore, more and more researchers have begun to focus on STAT5 (15)(16)(17)(18)(19). Evidence reveals that inhibition of STAT5 affects biological behavior of cancer cells.…”