Decreased expression of retinoid receptors in melanoma: Entailment in tumorigenesis and prognosis

Purpose: Retinoids inhibit proliferation and induce differentiation in melanoma cells. Retinoic acid receptors (RAR) and retinoid X receptors (RXR) mediate the various modulatory effects of retinoids in cells. We have studied the in situ expression of each RAR and RXR protein (alpha, beta, gamma) in a large series of melanocytic lesions and correlated the expression with clinicopathologic features and prognosis of the patients. Experimental Design: Tissue microarray blocks of 226 melanocytic lesions were semiquantitatively evaluated by immunohistochemistry for the cytoplasmic and nuclear expression of RAR and RXR protein (alpha, beta, gamma). Results: A significant decrease of RAR beta protein (P < 0.0001), nuclear expression of RAR gamma (P < 0.0001), and RXR alpha (P < 0.0001) was found in primary and metastatic melanomas as compared with nevi. Loss of nuclear immunoreactivity for RAR gamma (P = 0.048) and RXR alpha (P = 0.001) was observed in the lesions showing vertical growth pattern, In addition, in patients with concomitant loss of cytoplasmic staining for RAR alpha and RXR alpha, the probability of overall survival (log-rank test, P = 0.002) and disease-specific survival (log-rank test, P = 0.014) was significantly lower. Conclusions: Aberrant expression of retinoid receptors seems to be a frequent event in melanoma and suggests an impairment of the retinoid pathway in this cancer. Our data indicate the loss of retinoid receptor expression with melanoma progression and suggest a possible prognostic significance of the analysis of retinoid receptors in melanoma.