Tissue microarray analysis of signal transducers and activators of transcription 3 (Stat3) and phospho-Stat3 (Tyr705) in node-negative breast cancer shows nuclear localization is associated with a better prognosis.

PURPOSE Although a high frequency of tumors contain constitutively activated signal transducers and activators of transcription 3 (Stat3), its relationship to breast cancer and patient survival has not been determined in a large retrospective study of node-negative tumors. To further elucidate the role of Stat3 in breast cancers, the expression patterns of Stat3 and Phospho-tyrosine residue 705 (Tyr705) Stat3 were correlated with survival outcome and clinicopathological parameters in a large cohort of node-negative breast cancer tumors. EXPERIMENTAL DESIGN Immunohistochemical analysis of Stat3 and Phospho-Stat3 was performed on a breast cancer tissue microarray of 346 node-negative breast cancer specimens. These results were correlated with overall survival and other clinicopathological data. RESULTS Positive Stat3 cytoplasmic expression was seen in 69.2% of tumors, and positive Phospho-Stat3 (Tyr705) cytoplasmic expression was seen in 19.6% of tumors. Neither cytoplasmic expression showed significant association with survival or other clinical parameters. However, 23.1% of tumors had positive Stat3 nuclear expression, and those patients had a significantly improved short-term survival (P = 0.0332) at 5 years of follow-up. Upon analysis of positive Phospho-Stat3 (Tyr705) nuclear expression, seen in 43.5% of tumors, positive tumors had a significantly improved survival at both short-term 5-year survival (P = 0.0054) and long-term 20-year (P = 0.0376) survival analysis. Additionally, positive Phospho-Stat3 (Tyr705) nuclear expression is an independent prognostic marker of better overall survival node-negative breast cancer by multivariate analyses that included the variables of nuclear grade, Ki-67, estrogen receptor staining, progesterone receptor staining, Her2 staining, age, and tumor size. CONCLUSIONS These findings support a role for Stat3 and Phospho-Stat3 (Tyr705) overexpression in node-negative breast cancer and provide initial evidence that Phospho-Stat3 (Tyr705) may be a marker for improved overall survival independent of other prognostic markers.

[1]  H. Battifora.  The multitumor (sausage) tissue block: novel method for immunohistochemical antibody testing. , 1986, Laboratory investigation; a journal of technical methods and pathology.

[2]  J. Darnell,et al.  Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. , 1994, Science.

[3]  G. Stark,et al.  A major role for the protein tyrosine kinase JAK1 in the JAK/STAT signal transduction pathway in response to interleukin‐6. , 1995, The EMBO journal.

[4]  C. Watson,et al.  Elevated levels of members of the STAT family of transcription factors in breast carcinoma nuclear extracts. , 1995, British Journal of Cancer.

[5]  C. Watson,et al.  Edinburgh Research Explorer Differential activation of STATs 3 and 5 during mammary gland development , 2022 .

[6]  S. Akira,et al.  Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[7]  R. Jove,et al.  Role of epidermal growth factor receptor and STAT-3 activation in autonomous proliferation of SUM-102PT human breast cancer cells. , 1997, Cancer research.

[8]  R. Jove,et al.  Constitutive activation of Stat3 in fibroblasts transformed by diverse oncoproteins and in breast carcinoma cells. , 1997, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[9]  J. Turkson,et al.  Stat3 Activation by Src Induces Specific Gene Regulation and Is Required for Cell Transformation , 1998, Molecular and Cellular Biology.

[10]  J. Kononen,et al.  Tissue microarrays for high-throughput molecular profiling of tumor specimens , 1998, Nature Medicine.

[11]  J. Darnell,et al.  Stat3 Activation Is Required for Cellular Transformation by v-src , 1998, Molecular and Cellular Biology.

[12]  S. Akira,et al.  Suppression of epithelial apoptosis and delayed mammary gland involution in mice with a conditional knockout of Stat3. , 1999, Genes & development.

[13]  Christian A. Rees,et al.  Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  D. Rimm,et al.  Validation of Tissue Microarray Technology in Breast Carcinoma , 2000, Laboratory Investigation.

[15]  J. Bromberg.  Signal transducers and activators of transcription as regulators of growth, apoptosis and breast development , 2000, Breast Cancer Research.

[16]  J. Darnell,et al.  The role of STATs in transcriptional control and their impact on cellular function , 2000, Oncogene.

[17]  R. Reynolds,et al.  Elevated phosphorylation of AKT and Stat3 in prostate, breast, and cervical cancer cells. , 2000, International journal of oncology.

[18]  Jiayuh Lin,et al.  Constitutive activation of stat 3 oncogene product in human ovarian carcinoma cells. , 2000, Gynecologic oncology.

[19]  M. Bartoli,et al.  Vascular Endothelial Growth Factor Activates STAT Proteins in Aortic Endothelial Cells* , 2000, The Journal of Biological Chemistry.

[20]  J. Turkson,et al.  STAT proteins: novel molecular targets for cancer drug discovery , 2000, Oncogene.

[21]  D. Barnes,et al.  Multiple tissue core arrays in histopathology research: a validation study , 2000, The Journal of pathology.

[22]  S. Akira,et al.  The role of Stat3 in apoptosis and mammary gland involution. Conditional deletion of Stat3. , 2000, Advances in experimental medicine and biology.

[23]  T. Savarese,et al.  Increased expression of the interleukin-11 receptor and evidence of STAT3 activation in prostate carcinoma. , 2001, The American journal of pathology.

[24]  D L Rimm,et al.  Tissue microarray: a new technology for amplification of tissue resources. , 2001, Cancer journal.

[25]  E. Dreher,et al.  EGFR dependent expression of STAT3 (but not STAT1) in breast cancer. , 2001, International journal of oncology.

[26]  H. Moch,et al.  Tissue microarrays for rapid linking of molecular changes to clinical endpoints. , 2001, The American journal of pathology.

[27]  Z. Xia,et al.  Truncated STAT proteins are prevalent at relapse of acute myeloid leukemia. , 2001, Leukemia research.

[28]  Hua Yu,et al.  Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells , 2001, Oncogene.