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Src Kinase and Mitogen-Activated Protein Kinases in the Progression from Normal to Malignant Endometrium

Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio

Purpose: The purpose of this research was to determine whether a correlation exists between the levels of activated mitogen-activated protein kinase (MAPK) and Src kinases and the progression from normal to malignant endometrium.

Experimental Design: We measured total and phosphorylated levels for extracellular signal-regulated kinase 1/2, p38, stress-activated protein kinase/c-Jun NH₂-terminal kinase, and Src kinases from 33 frozen endometrial adenocarcinomas and 38 benign endometrial specimens by quantitation of signals from Western blots using antibodies against these kinases.

Results: Elevated phospho-extracellular signal-regulated kinase 1/2 (150 ± 40 versus 46 ± 7; P = 0.03), phospho-Src (28 ± 5 versus 4 ± 1), and phospho-p38 (131 ± 16 versus 27 ± 7; P < 0.001) was detected in benign versus malignant endometrium when the Western blot signal of activated kinase was normalized to total kinase levels and ß actin. A modest increase in active c-Jun NH₂-terminal kinase was detected in carcinoma versus benign specimens (51 ± 13 versus 43 ± 10; P = 0.8). Expression of total kinases (normalized to ß-actin) was higher in carcinoma versus benign specimens, respectively (extracellular signal-regulated kinase 1/2, 9 ± 2 versus 0.7 ± 0.1; Src, 7 ± 2 versus 0.4 ± 0.1; stress-activated protein kinase c-Jun NH₂-terminal kinase, 2 ± 0.4 versus 0.2 ± 0.02; P < 0.001; and p38, 1 ± 0.2 versus 0.4 ± 0.1; P < 0.01). Immunohistochemistry for active and total Src kinases and MAPKs detected positive staining in epithelial and stroma cells.

Conclusions: These data demonstrated that, in contrast with breast cancer, the progression from normal to malignant endometrium is not associated with activation of MAPK and Src kinases. Elevation of these active kinases in benign endometrium may contribute to endometrial resistance to the antiestrogen action of tamoxifen.

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