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

摘要

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.