Expression of KIT, EGFR, HER‐2 and tyrosine phosphorylation in undifferentiated thyroid carcinoma: Implication for a new therapeutic approach

Abstract

The KIT, epidermal growth factor receptor (EGFR) and HER-2 oncoproteins have tyrosine kinase activity and are molecular targets in human cancer therapy. To clarify the significance of KIT, EGFR, and HER-2 in undifferentiated thyroid carcinoma (UTC), the expression of these receptors and tyrosine phosphorylation was examined immunohistochemically in resected cases of UTC and papillary thyroid carcinoma (PTC). KIT, EGFR, and HER-2 were also examined at the protein and mRNA levels in five UTC cell lines. KIT expression (1+), EGFR overexpression (2+/3+), HER-2 expression (1+), and tyrosine phosphorylation were detected immunohistochemically in 40%, 70%, 10%, and 50% of the 10 UTC. In 20 PTC, KIT, EGFR, and HER-2 were not detected, but tyrosine phosphorylation was detected in 25% of cases. In the five UTC cell lines, KIT expression (1+), EGFR overexpression (3+), HER-2 expression (1+), and tyrosine phosphorylation were detected immunocytochemically in 60%, 100%, 20%, and 40%, respectively. Western blot analysis did not detect KIT expression, but did detect EGFR and HER-2 expression in all five cell lines. Real-time polymerase chain reaction detected KIT mRNA in two of the cell lines (40%), EGFR in five (100%), and HER-2 in three (60%). The present findings suggest that EGFR overexpression was involved in the proliferation and development of UTC and was frequently accompanied by tyrosine phosphorylation. Expression of KIT and HER-2 appeared to be weak but significant, suggesting a possible role in the development of UTC. Molecular therapies targeting KIT, EGFR, HER-2, and/or tyrosine phosphorylation might be indicated for UTC.

The role of oestrogen receptor α in human thyroid cancer: contributions from coregulatory proteins and the tyrosine kinase receptor HER2

“…These cells do, however, retain differentiated thyrocytic function and are responsive to growth factors. The anaplastic cell line, 8305C, was established from an undifferentiated thyroid and is positive for both EGFR and HER2 (Murakawa et al 2005). From cell cycle analysis, 8305C cells had a greater percentage of cells in the G 2 /M phase in comparison to the FTC-133 cells.…”

Antiproliferative and proapoptotic activity of CLM3, a novel multiple tyrosine kinase inhibitor, alone and in combination with SN-38 on endothelial and cancer cells

“…In order to improve the antineoplastic activity of CLM3, we presently investigated the effects of CLM3 in combination with SN-38 in EGFR and VEGFR-2 expressing human endothelial cell line HMVEC-d and in EGFR and RET expressing human thyroid cancer cell 8305C [50].…”

Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis

“…In agreement with this, EGFR and VEGFR2 overexpression has been shown to be closely correlated to advanced tumor stage, metastasis, and poor clinical outcome in several human cancers. With respect to thyroid carcinomas, EGFR overexpression has been detected in most anaplastic tumors (Schiff et al 2004, Wiseman et al 2007, Elliott et al 2008 and to a much lower extent in PTCs (Schiff et al 2004, Murakawa et al 2005, Mitsiades et al 2006, Lim et al 2007, Elliott et al 2008. In PTC, EGFR expression has been associated to poor prognosis (Akslen & Varhaug 1995, Chen et al 1999, although not always (Lim et al 2007), and recent studies have suggested that EGFR inhibitors might be active against anaplastic thyroid carcinomas (Lopez et al 2008).…”