Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure.

Abstract

PURPOSE:

To 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 METHODS:

Levels 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.

RESULTS:

Nuc-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 = 233) and quantitative immunofluorescence of a tissue microarray (cohort II; n = 291). Two distinct monoclonal antibodies gave concordant results. A progression array (cohort III; n = 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 = 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 = 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 < .001; TTR HR, 7.30; 95% CI, 2.34 to 22.78; P = .001). CONCLUSION Nuc-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.

• Authors: Amy R Peck, Agnieszka K Witkiewicz, Chengbao Liu, Ginger A Stringer, Alexander C Klimowicz, Edward Pequignot, Boris Freydin, Thai H Tran, Ning Yang, Anne L Rosenberg, Jeffrey A Hooke, Albert J Kovatich, Marja T Nevalainen, Craig D Shriver, Terry Hyslop, Guido Sauter, David L Rimm, Anthony M Magliocco, Hallgeir Rui
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 18 Pg. 2448-58 (Jun 20 2011) ISSN: 1527-7755 [Electronic] United States
• PMID: 21576635 (Publication Type: Comparative Study, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents, Hormonal
• Estrogen Receptor Modulators
• Neoplasm Proteins
• Nuclear Proteins
• STAT5 Transcription Factor
• STAT5A protein, human
• STAT5B protein, human
• Tumor Suppressor Proteins
• Phosphotyrosine

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents, Hormonal (pharmacology, therapeutic use)
• Breast Neoplasms (drug therapy, metabolism, mortality, pathology)
• Carcinoma, Ductal, Breast (drug therapy, metabolism, mortality, pathology)
• Carcinoma, Intraductal, Noninfiltrating (drug therapy, metabolism, mortality, pathology)
• Cohort Studies
• Disease Progression
• Disease-Free Survival
• Drug Resistance, Neoplasm
• Estrogen Receptor Modulators (pharmacology, therapeutic use)
• Female
• Humans
• Lymphatic Metastasis
• Middle Aged
• Neoplasm Proteins (chemistry, physiology)
• Nuclear Proteins (chemistry, physiology)
• Phosphorylation
• Phosphotyrosine (chemistry)
• Prognosis
• Protein Processing, Post-Translational
• STAT5 Transcription Factor (chemistry, physiology)
• Survival Analysis
• Treatment Failure
• Tumor Suppressor Proteins (chemistry, physiology)
• Young Adult