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  • Original Paper
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Disabled-2 inactivation is an early step in ovarian tumorigenicity

Oncogene volume 18, pages 3104–3113 (1999)Cite this article

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.

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Abbreviations

DAB:

3,3′-diaminobenzidine

DMEM:

Dulbeco's modified Eagle's Medium

DEPC:

Diethylpyrocarbonate

DOC-2:

Differentially expressed in Ovarian Carcinomas 2

EGF:

Epidermal Growth Factor

FBS:

fetal bovine serum

Grb2:

Growth Factor Receptor Binding Protein 2

MOPS:

3-morpholinopropane sulphonic acid

PRD:

proline-rich domain

PID:

phosphotyrosine interaction domain, or PTB

SH2 & SH3:

Src homology domain 2 & 3

SDS:

sodium dodicial sulphate

Sos:

Son of Sevenless

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Acknowledgements

The authors would like to thank Drs Elizabeth R Smith, Margaret Offermann, Mary Delong, and Kapil Bhalla for their critical reading, constructive critiques and valuable suggestions in preparation of this manuscript. We thank Dr Andrew Fischer and Ms Beth Sumpter for their assistance in tumor tissue collection, Ms Diane Lawson for her assistance in immunostaining. The studies were supported by grants R55 CA70783 and R01 CA75389 from NCI, NIH to XX Xu.

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Authors and Affiliations

  1. Department of Biochemistry and Winship Cancer Center, Emory University School of Medicine, Atlanta, 30322, Georgia, USA

    Zia Fazili, Wenping Sun, Stephen Mittelstaedt & Xiang-Xi Xu

  2. Department of Pathology, Emory University School of Medicine, Atlanta, 30322, Georgia, USA

    Cynthia Cohen

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  1. Zia Fazili
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Fazili, Z., Sun, W., Mittelstaedt, S. et al. Disabled-2 inactivation is an early step in ovarian tumorigenicity. Oncogene 18, 3104–3113 (1999). https://doi.org/10.1038/sj.onc.1202649

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