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Open Access Highly Accessed Research article

Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes

Amy R Peck1, Agnieszka K Witkiewicz2, Chengbao Liu1, Alexander C Klimowicz3, Ginger A Stringer4, Edward Pequignot4, Boris Freydin4, Ning Yang1, Adam Ertel4, Thai H Tran1, Melanie A Girondo1, Anne L Rosenberg5, Jeffrey A Hooke6, Albert J Kovatich7, Craig D Shriver8, David L Rimm9, Anthony M Magliocco10, Terry Hyslop4 and Hallgeir Rui12*

Author Affiliations

1 Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, 233 S. 10th Street, Philadelphia, PA 19107, USA

2 Department of Pathology, Thomas Jefferson University, 132 S. 10th Street, Philadelphia, PA 19107, USA

3 Department of Oncology, University of Calgary, 1331 29th St NW, Calgary, Alberta T2N 4N2, Canada

4 Division of Biostatistics, Thomas Jefferson University, 1015 Chestnut St, Philadelphia, PA 19107, USA

5 Department of Surgery, Thomas Jefferson University, 1100 Walnut Street, Philadelphia, PA 19107, USA

6 Breast Center, Walter Reed National Military Medical Center, 8901 Wisconsin Ave, Bethesda, MD 20889, USA

7 Department of Surgery, Walter Reed National Military Medical Center, 8901 Wisconsin Ave, Bethesda, MD 20889, USA

8 MDR Global Systems, LLC, 425 Park Place, Windber, PA 15963, USA

9 Department of Pathology, Yale University School of Medicine, 310 Cedar St, New Haven, CT 06520, USA

10 Department of Anatomical Pathology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA

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Breast Cancer Research 2012, 14:R130  doi:10.1186/bcr3328

Published: 4 October 2012

Abstract

Introduction

Signal transducer and activator of transcripton-5a (Stat5a) and its close homologue, Stat5b, mediate key physiological effects of prolactin and growth hormone in mammary glands. In breast cancer, loss of nuclear localized and tyrosine phosphorylated Stat5a/b is associated with poor prognosis and increased risk of antiestrogen therapy failure. Here we quantify for the first time levels of Stat5a and Stat5b over breast cancer progression, and explore their potential association with clinical outcome.

Methods

Stat5a and Stat5b protein levels were quantified in situ in breast-cancer progression material. Stat5a and Stat5b transcript levels in breast cancer were correlated with clinical outcome in 936 patients. Stat5a protein was further quantified in four archival cohorts totaling 686 patients with clinical outcome data by using multivariate models.

Results

Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared with normal epithelia. Low tumor levels of Stat5a but not Stat5b mRNA were associated with poor prognosis. Experimentally, only limited overlap between Stat5a- and Stat5b-modulated genes was found. In two cohorts of therapy-naïve, node-negative breast cancer patients, low nuclear Stat5a protein levels were an independent marker of poor prognosis. Multivariate analysis of two cohorts treated with antiestrogen monotherapy revealed that low nuclear Stat5a levels were associated with a more than fourfold risk of unfavorable outcome.

Conclusions

Loss of Stat5a represents a new independent marker of poor prognosis in node-negative breast cancer and may be a predictor of response to antiestrogen therapy if validated in randomized clinical trials.