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Breast Cancer Research and Treatment

, Volume 138, Issue 2, pp 407–413 | Cite as

Tumor STAT3 tyrosine phosphorylation status, as a predictor of benefit from adjuvant chemotherapy for breast cancer

  • Amir SonnenblickEmail author
  • Beatrice Uziely
  • Hovav Nechushtan
  • Luna Kadouri
  • Eithan Galun
  • Jonathan H. Axelrod
  • Daniela Katz
  • Hagit Daum
  • Tamar Hamburger
  • Bela Maly
  • Tanir M. Allweis
  • Tamar Peretz
Preclinical Study

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a point of convergence for numerous oncogenic signaling pathways. In breast cancer cell lines and xenograft models activated STAT3 participates in breast tumorigenesis, while studies in humans have demonstrated that phosphorylated (tyrosine705)-STAT3 is a marker of good prognosis in breast cancer. In order to resolve this paradox we hypothesized that in clinic, phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy; therefore the goal of this study was to determine the usefulness of phospho-STAT3 status as a predictor of benefit from adjuvant chemotherapy in breast cancer patients. Immunohistochemical analysis of phospho-STAT3 was performed on a tissue microarray of breast cancer specimens. The expression pattern of phospho-STAT3 was retrospectively correlated with pathological parameters and overall survival in patients who were or were not treated with adjuvant chemotherapy. Of 375 tissue specimens interpretable for phospho-STAT3, 134 (36 %) exhibited positive phospho-STAT3 nuclear expression. Among 234 patients who received adjuvant therapy, those with tumors displaying positive phospho-STAT3 nuclear expression had a better ten-year rate of overall survival than patients with tumors displaying negative phospho-STAT3 nuclear expression (P = 0.001). Among patients who did not received adjuvant chemotherapy, positive phospho-STAT3 nuclear status was not correlated with increased overall survival (P = 0.54). Positive phospho-STAT3 was correlated with improved overall survival only among patients who received adjuvant chemotherapy in a multivariate analysis adjusted for stage, grade, hormonal status, Her2 status, and age, irrespective of the chemotherapy regimen received (hazard ratio for death, 0.35 [95 % CI 0.188–0.667]; P = 0.001). These findings support the role of phospho-STAT3 as a marker of favorable outcome in breast cancer patients treated with adjuvant chemotherapy. Whether phospho-STAT3 has a predictive role of benefit from adjuvant chemotherapy has to be validated on prospective, randomized, controlled studies.

Keywords

STAT3 Tyrosine phosphorylation Predictive marker Adjuvant chemotherapy Breast cancer 

Abbreviations

STAT3

Signal transducer and activator of transcription 3

ER

Estrogen receptor

HR

Hormonal receptor

TIMP1

Tissue inhibitor of metalloproteinase-1

CAF

Cyclophophamide adriamicin 5FU

CMF

Cyclophophamide methotrexate 5FU

Notes

Acknowledgments

This study was supported by grants from Hadassah medical center (AS), ICA—Israeli cancer association (AS), the ROSETREES TRUST (AS), APF—American physicians’ fellowship for medicine in Israel (AS). David S. Lando Memorial fund (AS), Raymond F. Schinazi International program (AS), Deutsche Forschungsgemeinschaft, Bonn, Germany SFB841 (EG).

Conflict of interest

All authors indicated no financial or other conflicting interests that are relevant to the subject matter under consideration in this article.

Supplementary material

10549_2013_2453_MOESM1_ESM.doc (28 kb)
Supplementary material 1 (DOC 27 kb)
10549_2013_2453_MOESM2_ESM.doc (26 kb)
Supplementary material 2 (DOC 26 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Amir Sonnenblick
    • 1
    • 2
    Email author
  • Beatrice Uziely
    • 1
  • Hovav Nechushtan
    • 1
  • Luna Kadouri
    • 1
  • Eithan Galun
    • 2
  • Jonathan H. Axelrod
    • 2
  • Daniela Katz
    • 1
  • Hagit Daum
    • 3
  • Tamar Hamburger
    • 1
  • Bela Maly
    • 4
  • Tanir M. Allweis
    • 5
  • Tamar Peretz
    • 1
  1. 1.Sharett Institute of OncologyHadassah-Hebrew University Medical CenterJerusalemIsrael
  2. 2.Goldyne Savad Institute of Gene TherapyHadassah-Hebrew University Medical CenterJerusalemIsrael
  3. 3.Department of Obstetrics and GynecologyHadassah-Hebrew University Medical CenterJerusalemIsrael
  4. 4.Department of PathologyHadassah-Hebrew University HospitalJerusalemIsrael
  5. 5.Department of SurgeryKaplan Medical CenterRehovotIsrael

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