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

  • Preclinical Study
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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.

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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

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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.

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Authors and Affiliations

  1. Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Ein Kerem, P.O. Box 12000, Jerusalem, 91120, Israel

    Amir Sonnenblick, Beatrice Uziely, Hovav Nechushtan, Luna Kadouri, Daniela Katz, Tamar Hamburger & Tamar Peretz

  2. Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Amir Sonnenblick, Eithan Galun & Jonathan H. Axelrod

  3. Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Mt Scopus, Jerusalem, Israel

    Hagit Daum

  4. Department of Pathology, Hadassah-Hebrew University Hospital, Jerusalem, Israel

    Bela Maly

  5. Department of Surgery, Kaplan Medical Center, Rehovot, Israel

    Tanir M. Allweis

Authors
  1. Amir Sonnenblick
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  2. Beatrice Uziely
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  3. Hovav Nechushtan
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  4. Luna Kadouri
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  5. Eithan Galun
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  6. Jonathan H. Axelrod
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  7. Daniela Katz
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  8. Hagit Daum
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  9. Tamar Hamburger
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  10. Bela Maly
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  11. Tanir M. Allweis
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  12. Tamar Peretz
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Corresponding author

Correspondence to Amir Sonnenblick.

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Sonnenblick, A., Uziely, B., Nechushtan, H. et al. Tumor STAT3 tyrosine phosphorylation status, as a predictor of benefit from adjuvant chemotherapy for breast cancer. Breast Cancer Res Treat 138, 407–413 (2013). https://doi.org/10.1007/s10549-013-2453-x

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  • DOI: https://doi.org/10.1007/s10549-013-2453-x

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