Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes
A partir d'échantillons tumoraux provenant de 5 cohortes incluant au total 1 622 patientes atteintes d'un cancer du sein, cette étude montre qu'un faible niveau d'expression tumorale de la protéine Stat5a est associé à la progression de la maladie et à un pronostic défavorable
INTRODUCTION:Signal transducer and activator of transcripton-5a (Stat5a) and its close homolog, 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 a 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 using multivariate models.RESULTS:Protein levels of Stat5a but not Stat5b were reduced in primary breast cancer and lymph node metastases compared to 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-naive, 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 more than 4-fold 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.
Breast Cancer Research , article en libre accès, 2011