Cellular retinol binding protein-1 expression in endometrial hyperplasia and carcinoma: diagnostic and possible therapeutic implications

Cellular retinol binding protein-1 (CRBP-1) contributes to the maintenance of the differentiative state of endometrial glandular cells through the regulation of bioavailability of retinol and derivatives, but its role in endometrial oncogenetic process remains unclear. Antibodies to CRBP-1, estrogen and progesterone receptors (ER and PR) were applied to paraffin sections of proliferative (n = 10) and secretory endometrium (n = 9), and to endometrial polyps (n = 6), simple (n = 7), complex (n = 3) and atypical endometrial hyperplasias (n = 9) as well as to 47 endometrioid carcinomas of different histological grade (G) (G1, n = 18; G2, n = 19; G3, n = 10). Four serous and two clear cell carcinomas were also examined. In glandular cells, CRBP-1 positivity was mainly cytoplasmic and rarely in the nuclei. CRBP-1 immunodetection was weakly positive in proliferative and low and focal in secretory endometrium and higher in atypical as compared to simple and complex hyperplasias. CRBP-1 expression in G1 endometrioid carcinomas was similar to that in atypical hyperplasias. In the latter, the highest CRBP-1 expression was observed in areas of squamous differentiation. Semiquantitative evaluation revealed a significant decrease of cytoplasmic CRBP-1 immunoreactivity with the increase of tumor grade. Among G3 endometrioid carcinomas, 60% were CRBP-1 negative, whereas the remaining cases showed a very low and focal positivity. Serous carcinomas were also CRBP-1 negative. When areas of different grading were present within the same tumor, less differentiated areas retained a lower CRBP- 1 immunoreaction. The progressive decrease of CRBP-1 paralleled that of ER and PR immunodetection. RT-PCR in eight endometrioid carcinomas suggested a decrease of CRBP-1 with the increase of tumor grade also at transcriptional level. Our results indicate that CRBP-1 immunodetection may constitute an additional tool for histological grading of endometrial carcinoma. The CRBP-1 loss during the progression of endometrial cancer suggests a new potential target for pharmacological strategies aimed to counteract its progression by increased intracellular retinol bioavailability.