Stat5: From Breast Development to Cancer Prognosis, Prediction, and Progression

Abstract

Signal transducer and activator of transcription (STAT) proteins transmit signals from extracellular polypeptides, through transmembrane receptors, directly to target gene promoters in the nucleus resulting in genetic reprogramming of the target cell. There are seven STAT genes in mammals (1, 2, 3, 4, 5A, 5B, and 6) derived phylogenetically from an ancestral gene (Stat93E) that first appeared in Drosophila. STAT proteins are latent transcription factors activated by tyrosine phosphorylation following recruitment to ligand-activated receptor complexes. Tyrosine phosphorylation allows tail-to-tail dimerizationleadingtotheiraccumulationwithinthenucleus.KnockoutofSTAT genes in mice has established their key roles in the distinct responses elicitedbyspecificpolypeptidehormoneligands,withfidelityinresponses being transmitted, in part, through specificity of binding of each STAT Src-homology 2 (SH2) domain to phosphotyrosine-containing motifs located within ligand-activated receptor complexes. Stat5 is encoded by two highly homologous genes—5A and 5B—which, along with Stat3, are clustered on chromosome 17q in humans (chromosome 11 in mice). Gene targeting studies in mice demonstrated interplay between Stat5 and Stat3 in normal breast biology: Stat5A is required for terminal mammary gland differentiation and lactogenesis, while Stat3 is required for breast involution after weaning. Stat5B-deficient mice did not demonstrate a breast phenotype. Constitutively activated STAT proteins, in particular Stat3 and Stat5, have been demonstrated to directly contribute to oncogenesis, in part, by stimulating proliferation and preventing apoptosis in various types of tumor cells. The role for Stat3 and Stat5 in the pathogenesis of human breast cancers is becoming increasingly recognized. There is evidence of increased STAT protein binding in the nuclei of breast cancer compared with the normal tissue of benign lesions. Several studies have shown the role of Stat3 as a prognostic factor in breast cancer. In addition, previous studies have shown an association between Stat5 nuclear localization/ phosphorylation and improved survival. These previous studies that suggest the prognostic significance of Stat5 were conducted in cohorts that previously received some form of adjuvant therapy in a percentage of patients. There have been other published studies that allude to the predictive significance of Stat5. In a study by Yamashita et al, patients with Stat5–positive primary breast tumors had a significantly improved response to endocrine therapy. In the current article by Peck et al accompanying this editorial, a comprehensive study of the utility of Stat5 is comprehensively delineated, including its role as a prognostic marker in the absence of any systemic therapy, in the progression from normal to in situ through invasive ductal cancer and nodal metastases, and finally, as a predictive marker of endocrine resistance. Firstly, the role of Stat5 as a prognostic marker was clearly defined in this article. In two independent cohorts of patients who did not receive adjuvant systemic therapy, phosphorylated and nuclear localized Stat5 (NUC-pYStat5) was found to be an independent marker of outcome in patients with lymph node–negative breast cancer with a total of close to 500 tumor specimens examined. Patients with reduced NUC-pYStat5 expression had approximately a 2.5-fold increase risk of disease recurrence and approximately a 2.4-fold risk of dying of breast cancer. This is the first publication, to our knowledge, that comprehensively addressed the role of NUC-pYStat5 as an independent marker of prognosis in patients with untreated node-negative breast cancer. Secondly, Peck et al define the role of Stat5 in cancer progression. Levels of NUC-pYStat5 quantitated by automated quantitative analysis (AQUA), decreased as the disease progressed from normal to in situ, to invasive, and then to nodal metastases. Thirdly, and perhaps most importantly, Peck et al found that the absence of detectable NUC-pYStat5 in tumors of patients treated with antiestrogen therapy, was associated with poor breast cancer–specific survival. Multivariate analysis showed that patients with the lowest levels of NUC-pYStat5 had nearly a seven-fold increased risk of dying from breast cancer despite antiestrogen therapy. Collectively, these consistent observations strongly suggest that low levels of NUC-pYStat5 are not only a poor prognostic factor that is associated with cancer progression, but also predicts for failure to respond to antiestrogen treatment. This final observation is critically important. Close to one third of patients with estrogen receptor– positive breast cancers fail to respond to antiestrogen therapy as a consequence of either inherent or acquired resistance. Many markers including human epidermal growth factor receptor 2 (HER2) suggest cross-talk between several pathways. However, most of these pathways, including HER2, are poor predictive markers of response to antiestrogen therapy. In contrast, NUC-pYStat5 may add to selecting patients who are unlikely to respond to antiestrogen therapy even though their tumors express estrogen receptor. In conclusion, this work supports the role of Stat5 signaling in cancer progression, and provides strong evidence for this marker as a JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S VOLUME 29 NUMBER 18 JUNE 2