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Non-receptor tyrosine kinase 2 reaches its lowest expression levels in human breast cancer during regional nodal metastasis

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Abstract

Almost half of breast Ductal Carcinoma in situ are likely to remain non threatening in situ lesions with no invasion to the surrounding stroma and no metastases. The majority of focal disruptions in myoepithelial (ME) cell layers indicative of invasion onset were found to be overlying epithelial cell clusters with no or substantially reduced estrogen receptor α (ERα) expression. Here we report the down-regulation of tyrosine kinase-2 (TYK2) and up-regulation of strumpellin expression, among other proteins in ERα(−) cells located at disrupted ME layers compared to adjacent ERα(+) cells overlying an intact myoepithelial layer. ERα(+) and ERα(−) cells were microdissected from the same in vivo human breast cancer tissues, proteins were extracted and separated utilizing Differential in-Gel Electrophoresis followed by trypsin digestion, MALDI-TOF analysis, and protein identification. Proteins expressed by ERα(−) cell clusters were found to express higher levels of strumpellin that binds to valosin-containing protein (VCP) to slow-down wound closure and promote growth; and lower levels of TYK2, a jak protein necessary for lineage specific differentiation. TYK2 levels were further analyzed by immunohistochemistry in a cohort composed of 70 patients with broad clinical characteristics. TYK2 levels were minimal in TxN1M0 breast cancers which is the stage where the initial regional lymph node metastasis is observed. Our data highlight the role of TYK2 downregulation in breast cancer cell de-differentitation and initiation of regional metastasis. In addition, the aggressiveness of the ERα(−) cell clusters compared to ERα(+) ones present in the same duct of the same patient was confirmed.

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Acknowledgment

This work was supported in part by a grant from the Charles and Mary Latham Fund to ZJ Sahab, grant BCTR0504465 from the Susan G. Komen Breast Cancer Foundation, grants from the Florida Breast Cancer Coalition Research Foundation, the Elsa U. Pardee Foundation, and the Florida State University to Q.-X. Sang, and a grant BCTR0706983 from the Susan G. Komen Breast Cancer Foundation, grant 2006CB910505 from the Ministry of Chinese Science and Technology to Y.-G. Man, and grants R01CA129813 and P01 CA130821 to SW Byers. The authors wish to acknowledge the support of the following Lombardi Comprehensive Cancer Center Core Facilities (NIH P30 CA51008): Tissue culture, Histopathology, Microscopy, and Proteomics shared resources.

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL, 32306-4390, USA

    Qing-Xiang Amy Sang

  2. The Diagnostic and Translational Research Center, The Henry Jackson Foundation for the Advancement of Military Medicine, Gaithersburg, MD, 20789, USA

    Yan-Gao Man

  3. Walter Reed Army Medical Center, Washington, DC, 20307, USA

    Yan-Gao Man

  4. Jilin University, Changchun, Jilin, China

    Yan-Gao Man

  5. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd NW Suite E415, Washington, DC, 20007, USA

    You Me Sung, Zahraa I. Khamis, Mi-Hye Lee, Stephen W. Byers & Ziad J. Sahab

  6. Proteomics and Metabolomics Shared Resource, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, 20007, USA

    Lihua Zhang

Authors
  1. Qing-Xiang Amy Sang
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  2. Yan-Gao Man
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  4. Zahraa I. Khamis
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  5. Lihua Zhang
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  6. Mi-Hye Lee
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  7. Stephen W. Byers
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  8. Ziad J. Sahab
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Corresponding author

Correspondence to Ziad J. Sahab.

Additional information

Qing-Xiang Amy Sang, Yan-Gao Man, You Me Sung have contributed equally to this work

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Sang, QX.A., Man, YG., Sung, Y.M. et al. Non-receptor tyrosine kinase 2 reaches its lowest expression levels in human breast cancer during regional nodal metastasis. Clin Exp Metastasis 29, 143–153 (2012). https://doi.org/10.1007/s10585-011-9437-1

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  • DOI: https://doi.org/10.1007/s10585-011-9437-1

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