Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer
Signal transducer and activator of transcription 3 (Stat3) is responsible for many aspects of normal development and contributes to the development and progression of cancer through regulating epithelial cell identity and cancer stem cells. In breast cancer, Stat3 is associated with triple-negative...
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| Format: | Article |
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Frontiers Media S.A.
2022-08-01
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| Series: | Pathology and Oncology Research |
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| Online Access: | https://www.por-journal.com/articles/10.3389/pore.2022.1610592/full |
| _version_ | 1797221019762556928 |
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| author | Michaela Stenckova Michaela Stenckova Rudolf Nenutil Borivoj Vojtesek Philip J. Coates |
| author_facet | Michaela Stenckova Michaela Stenckova Rudolf Nenutil Borivoj Vojtesek Philip J. Coates |
| author_sort | Michaela Stenckova |
| collection | DOAJ |
| description | Signal transducer and activator of transcription 3 (Stat3) is responsible for many aspects of normal development and contributes to the development and progression of cancer through regulating epithelial cell identity and cancer stem cells. In breast cancer, Stat3 is associated with triple-negative breast cancers (TNBC) and its function has been related to the activation of p63, itself a marker of basal-like TNBC and a master regulator of stem cell activities. Stat3 activation is controlled by dual phosphorylation at tyrosine 705 (pTyr705) and serine 727 (pSer727), although it is unclear whether these have equivalent effects, and whether they are related or independent events. To address these issues, we investigated Stat3 phosphorylation at the two sites by immunohistochemistry in 173 patients with TNBC. Stat3 phosphorylation was assessed by automated quantitative measurements of digitized scanned images and classified into four categories based on histoscore. The results were analyzed for associations with multiple markers of tumor phenotype, proliferation, BRCA status, and clinicopathological characteristics. We show that the levels of pTyr705- and pSer727-Stat3 were independent in 34% of tumors. High pTyr705-Stat3 levels were associated with the luminal differentiation markers ERβ/AR and MUC1, whereas tumors with high levels of pSer727-Stat3 were more likely to be positive for the basal marker CK5/6, but were independent of p63 and were EGFR negative. Combined high pSer727- and low Tyr705-Stat3 phosphorylation associated with basal-like cancer. Although high Stat3 phosphorylation levels were associated with less aggressive tumor characteristics, they did not associate with improved survival, indicating that Stat3 phosphorylation is an unfavorable indicator for tumors with an otherwise good prognosis according to clinicopathological characteristics. These findings also show that pTyr705-Stat3 and pSer727-Stat3 associate with specific breast tumor phenotypes, implying that they exert distinct functional activities in breast cancer. |
| first_indexed | 2024-04-24T12:58:47Z |
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| institution | Directory Open Access Journal |
| issn | 1532-2807 |
| language | English |
| last_indexed | 2024-04-24T12:58:47Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Pathology and Oncology Research |
| spelling | doaj.art-8d7cd23200ef4d5293bbb154d32f90cb2024-04-05T16:23:30ZengFrontiers Media S.A.Pathology and Oncology Research1532-28072022-08-012810.3389/pore.2022.16105921610592Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast CancerMichaela Stenckova0Michaela Stenckova1Rudolf Nenutil2Borivoj Vojtesek3Philip J. Coates4Masaryk Memorial Cancer Institute, Research Center for Applied Molecular Oncology (RECAMO), Brno, CzechiaDepartment of Experimental Biology, Faculty of Science, Masaryk University, Brno, CzechiaMasaryk Memorial Cancer Institute, Research Center for Applied Molecular Oncology (RECAMO), Brno, CzechiaMasaryk Memorial Cancer Institute, Research Center for Applied Molecular Oncology (RECAMO), Brno, CzechiaMasaryk Memorial Cancer Institute, Research Center for Applied Molecular Oncology (RECAMO), Brno, CzechiaSignal transducer and activator of transcription 3 (Stat3) is responsible for many aspects of normal development and contributes to the development and progression of cancer through regulating epithelial cell identity and cancer stem cells. In breast cancer, Stat3 is associated with triple-negative breast cancers (TNBC) and its function has been related to the activation of p63, itself a marker of basal-like TNBC and a master regulator of stem cell activities. Stat3 activation is controlled by dual phosphorylation at tyrosine 705 (pTyr705) and serine 727 (pSer727), although it is unclear whether these have equivalent effects, and whether they are related or independent events. To address these issues, we investigated Stat3 phosphorylation at the two sites by immunohistochemistry in 173 patients with TNBC. Stat3 phosphorylation was assessed by automated quantitative measurements of digitized scanned images and classified into four categories based on histoscore. The results were analyzed for associations with multiple markers of tumor phenotype, proliferation, BRCA status, and clinicopathological characteristics. We show that the levels of pTyr705- and pSer727-Stat3 were independent in 34% of tumors. High pTyr705-Stat3 levels were associated with the luminal differentiation markers ERβ/AR and MUC1, whereas tumors with high levels of pSer727-Stat3 were more likely to be positive for the basal marker CK5/6, but were independent of p63 and were EGFR negative. Combined high pSer727- and low Tyr705-Stat3 phosphorylation associated with basal-like cancer. Although high Stat3 phosphorylation levels were associated with less aggressive tumor characteristics, they did not associate with improved survival, indicating that Stat3 phosphorylation is an unfavorable indicator for tumors with an otherwise good prognosis according to clinicopathological characteristics. These findings also show that pTyr705-Stat3 and pSer727-Stat3 associate with specific breast tumor phenotypes, implying that they exert distinct functional activities in breast cancer.https://www.por-journal.com/articles/10.3389/pore.2022.1610592/fullclinicopathological characteristicstriple-negative breast cancerStat3 tyrosine phosphorylationStat3 serine phosphorylationtumor cell phenotypes |
| spellingShingle | Michaela Stenckova Michaela Stenckova Rudolf Nenutil Borivoj Vojtesek Philip J. Coates Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer Pathology and Oncology Research clinicopathological characteristics triple-negative breast cancer Stat3 tyrosine phosphorylation Stat3 serine phosphorylation tumor cell phenotypes |
| title | Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer |
| title_full | Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer |
| title_fullStr | Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer |
| title_full_unstemmed | Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer |
| title_short | Stat3 Tyrosine 705 and Serine 727 Phosphorylation Associate With Clinicopathological Characteristics and Distinct Tumor Cell Phenotypes in Triple-Negative Breast Cancer |
| title_sort | stat3 tyrosine 705 and serine 727 phosphorylation associate with clinicopathological characteristics and distinct tumor cell phenotypes in triple negative breast cancer |
| topic | clinicopathological characteristics triple-negative breast cancer Stat3 tyrosine phosphorylation Stat3 serine phosphorylation tumor cell phenotypes |
| url | https://www.por-journal.com/articles/10.3389/pore.2022.1610592/full |
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