TY - JOUR
T1 - Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes
AU - Peck, Amy R.
AU - Witkiewicz, Agnieszka K.
AU - Liu, Chengbao
AU - Klimowicz, Alexander C.
AU - Stringer, Ginger A.
AU - Pequignot, Edward
AU - Freydin, Boris
AU - Yang, Ning
AU - Ertel, Adam
AU - Tran, Thai H.
AU - Girondo, Melanie A.
AU - Rosenberg, Anne L.
AU - Hooke, Jeffrey A.
AU - Kovatich, Albert J.
AU - Shriver, Craig D.
AU - Rimm, David L.
AU - Magliocco, Anthony M.
AU - Hyslop, Terry
AU - Rui, Hallgeir
N1 - Funding Information:
Whole-tissue sections and clinical data for Material III were generously provided by the National Cancer Institute Cooperative Breast Cancer Tissue Resource. We thank Eva Andersson for expert technical help with immunostaining of sections of Material III. This work was supported by NIH grants R01-CA101841 and R01-CA118740 (H.R.), Komen for the Cure Promise grant KG091116 (HR, AKW, CL, JAH, AE, AJK, CDS, MAG, TH), DOD CDMRP Predoctoral Fellowship (ARP), and NCI Support grant 1P30CA56036 to the Kimmel Cancer Center. The Project is funded, in part, under a Commonwealth University Research Enhancement Program grant with the Pennsylvania Department of Health (HR). The Department specifically disclaims responsibility for any analyses, interpretations, or conclusions. The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army (DOA), Department of Defense (DOD), or US Government.
PY - 2012/10/4
Y1 - 2012/10/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866893124&partnerID=8YFLogxK
U2 - 10.1186/bcr3328
DO - 10.1186/bcr3328
M3 - Article
C2 - 23036105
AN - SCOPUS:84866893124
SN - 1465-5411
VL - 14
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 5
M1 - R130
ER -