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

Amy R. Peck, Agnieszka K. Witkiewicz, Chengbao Liu, Alexander C. Klimowicz, Ginger A. Stringer, Edward Pequignot, Boris Freydin, Ning Yang, Adam Ertel, Thai H. Tran, Melanie A. Girondo, Anne L. Rosenberg, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, David L. Rimm, Anthony M. Magliocco, Terry Hyslop, Hallgeir Rui

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberR130
JournalBreast Cancer Research
Volume14
Issue number5
DOIs
StatePublished - Oct 4 2012

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Transducers
Breast Neoplasms
Neoplasms
Proteins
Estrogen Receptor Modulators
Human Mammary Glands
Prolactin
Growth Hormone
Tyrosine
Therapeutics
Multivariate Analysis
Epithelium
Randomized Controlled Trials
Lymph Nodes
Neoplasm Metastasis
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes. / Peck, Amy R.; Witkiewicz, Agnieszka K.; Liu, Chengbao; Klimowicz, Alexander C.; Stringer, Ginger A.; Pequignot, Edward; Freydin, Boris; Yang, Ning; Ertel, Adam; Tran, Thai H.; Girondo, Melanie A.; Rosenberg, Anne L.; Hooke, Jeffrey A.; Kovatich, Albert J.; Shriver, Craig D.; Rimm, David L.; Magliocco, Anthony M.; Hyslop, Terry; Rui, Hallgeir.

In: Breast Cancer Research, Vol. 14, No. 5, R130, 04.10.2012.

Research output: Contribution to journalArticle

Peck, AR, Witkiewicz, AK, Liu, C, Klimowicz, AC, Stringer, GA, Pequignot, E, Freydin, B, Yang, N, Ertel, A, Tran, TH, Girondo, MA, Rosenberg, AL, Hooke, JA, Kovatich, AJ, Shriver, CD, Rimm, DL, Magliocco, AM, Hyslop, T & Rui, H 2012, 'Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes', Breast Cancer Research, vol. 14, no. 5, R130. https://doi.org/10.1186/bcr3328
Peck, Amy R. ; Witkiewicz, Agnieszka K. ; Liu, Chengbao ; Klimowicz, Alexander C. ; Stringer, Ginger A. ; Pequignot, Edward ; Freydin, Boris ; Yang, Ning ; Ertel, Adam ; Tran, Thai H. ; Girondo, Melanie A. ; Rosenberg, Anne L. ; Hooke, Jeffrey A. ; Kovatich, Albert J. ; Shriver, Craig D. ; Rimm, David L. ; Magliocco, Anthony M. ; Hyslop, Terry ; Rui, Hallgeir. / Low levels of Stat5a protein in breast cancer are associated with tumor progression and unfavorable clinical outcomes. In: Breast Cancer Research. 2012 ; Vol. 14, No. 5.
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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-na{\"i}ve, 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.",
author = "Peck, {Amy R.} and Witkiewicz, {Agnieszka K.} and Chengbao Liu and Klimowicz, {Alexander C.} and Stringer, {Ginger A.} and Edward Pequignot and Boris Freydin and Ning Yang and Adam Ertel and Tran, {Thai H.} and Girondo, {Melanie A.} and Rosenberg, {Anne L.} and Hooke, {Jeffrey A.} and Kovatich, {Albert J.} and Shriver, {Craig D.} and Rimm, {David L.} and Magliocco, {Anthony M.} and Terry Hyslop and Hallgeir Rui",
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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

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.

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U2 - 10.1186/bcr3328

DO - 10.1186/bcr3328

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JO - Breast Cancer Research

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