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Decreased Expression of Retinoic Acid Receptors, Transforming Growth Factor ß, Involucrin, and Cornifin in Cervical Intraepithelial Neoplasia¹

Departments of Clinical Cancer Prevention [X-C. X.], Gynecologic Oncology [M. F. M.], Pathology [E. S.], and Thoracic/Head and Neck Medical Oncology [R. L.], The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, and Laboratory of Pulmonary Pathobiology, National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 [A. J.]

Cervical intraepithelial neoplasia (CIN) I, II, and III represent a spectrum of premalignant epithelial changes and are ideal targets for application of chemoprevention strategies. Intermediate end point biomarkers are increasingly being used as surrogate end points to monitor clinical chemoprevention trials. To identify potential biomarkers in cervical epithelium, we analyzed the expression of nuclear retinoic acid receptor (RAR) mRNA by in situ hybridization, involucrin, cornifin, and transforming growth factors (TGFs) ß1 and ß2 by immunohistochemistry in cervical specimens, which contained adjacent normal epithelium and CIN lesions from 52 patients. These biomarkers were expressed in all adjacent normal cervical epithelia, whereas all CIN lesions including CIN I, CIN II, and CIN III exhibited decreased expression of RAR- by 55.8%, RAR-ß by 64.7%, RAR- by 54.9%, involucrin by 80.8%, cornifin by 88.5%, TGF-ß1 by 89.7%, and TGF-ß2 by 85.7%. Viewed as a whole, these biomarkers were down-regulated in 100% of the CIN lesions. Because all of these biomarkers can be modulated in vitro by retinoids, they may serve as intermediate biomarkers for retinoid chemoprevention trials in the patients with CIN lesions.

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