Disabled-2 inactivation is an early step in ovarian tumorigenicity

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Abstract
Disabled-2 (Dab2) functions in mitogenic signal transduction pathway, and is frequently activated by homozygous gene deletion in tumors, suggesting that Dab2 is a candidate tumor suppressor. Here, we surveyed the expression of Dab2, and report that Dab2 is expressed in a variety of tissues, and the level of expression is particularly high in ovary and breast. Dab2 expression was also detected in immortalized breast and ovarian epithelial cells. However, in more than a dozen established tumor cell lines derived from breast and ovarian epithelial tumors examined by Western blotting, Dab2 expression was undetectable in 90% of these cell lines. Histological staining of human ovarian tissues with specific anti-Dab2 antibodies indicated that Dab2 is highly expressed in the surface epithelial layer. In an immunohistological study of 26 ovarian carcinomas, 22 (85%) of the tumors were found to lose the expression of Dab2 in the tumor cells, which are epithelial origin. Loss of Dab2 expression is not correlated with tumor grade, suggesting that Dab2 is lost in an early stage of tumorigenicity. Indeed, loss of Dab2 correlates closely with morphological transformation of the surface epithelial cells. Additionally, loss of Dab2 protein occurs in hyperproliferative, but histological benign ovarian epithelium, suggesting that loss of Dab2 occurs in pre-malignant lesions. Thus, this study indicates that the loss of Dab2 expression is correlated with tumorigenicity of the cells disregarding the grade of the tumors, and loss of Dab2 expression is an early event in ovarian malignancies.