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

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 (DIGE) 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 (IHC) 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.

Establishing the role of tyrosine kinase 2 in cancer

“…In this model of breast cancer, myeloid-derived suppressor cells (MDSCs) seem to be more effective in Tyk2-deficient mice that in wild-type animals. In bioptic material from breast cancer patients TYK2 appeared to be downregulated, hence consistently influencing cell de-differentiation and the initiation of regional metastases 42 . The function of CD4 + T cells, CD8 + T cells an NK cells was not altered in these mice.…”

TYK2: An Upstream Kinase of STATs in Cancer

“…The important role of TYK2 in immune-surveillance is also in line with findings in patients who carry mutated TYK2 alleles which lead to loss of TYK2, lowered TYK2 levels [46], or expression of kinase-inactive TYK2 [47,48,49], and that show primarily immunodeficiencies. Nonetheless, proteomics suggested that low TYK2 facilitates local metastasis in breast cancer [50], and a comprehensive screen for protein tyrosine kinase variants in numerous cancer cell lines identified splice variants that render TYK2 inactive [51]. On a molecular mechanistic level, the cell intrinsic tumor-promoting consequences of low TYK2 or LOF of TYK2 currently remain elusive.…”

“…This regulatory loop has not yet been studied in the context of carcinogenesis. Furthermore, knockdown of TYK2 reduced migration of breast cancer cell lines [50].…”

Emerging Roles of Atypical Dual Specificity Phosphatases in Cancer

“…The ability of DUSP3 to inhibit STAT5 transcriptional activity may have consequences in cancer cell biology, since STAT5 activity is known to promote cancer by transcriptionally regulating genes involved in proliferation and survival [45], therefore loss of DUSP3 activity could possibly result in increased STAT5 activity thereby promoting cancer development. Furthermore, TYK2 has a suggested role in breast cancer metastasis, as analysis of 140 tissue samples from 70 breast cancer patients revealed that TYK2 protein levels are reduced in tumors that have metastasized to the regional lymph nodes [46]. Additionally, knock-down of tyk2 in the MCF10A breast epithelial cell line decreased cell migration and invasion [46].…”

“…Furthermore, TYK2 has a suggested role in breast cancer metastasis, as analysis of 140 tissue samples from 70 breast cancer patients revealed that TYK2 protein levels are reduced in tumors that have metastasized to the regional lymph nodes [46]. Additionally, knock-down of tyk2 in the MCF10A breast epithelial cell line decreased cell migration and invasion [46]. Whether loss of TYK2 promotes metastasis, migration, and invasion due to reduced DUSP3 activity remains to be determined DUSP3's activity is additionally activated by the pseudokinase, Vaccinia-related kinase 3 (VRK3) [47], whose expression is down-regulated in colorectal cancer [48].…”