Relative expression of progesterone receptors A and B in endometrioid cancers of the endometrium

The nuclear receptor for the female hormone progesterone (PR) is widely exp ressed in uterine cancer. PR is expressed as two proteins (PRA and PRB) wit h different functions, and in vitro evidence reveals PRA to inhibit PRB fun ction, so the cellular ratio of PRA:PRB is likely to be an important determ inant of progesterone action. The relative expression of PRA and B and thei r involvement in the pathogenesis of endometrial cancer is not known. The a ims of this study were to determine PRA and B expression by dual immunofluo rescent histochemistry in endometrial adenocarcinomas compared with express ion in normal and hyperplastic glands, and to correlate expression in tumor s with clinical features including grade. Significantly lower PR levels wer e found in tumors compared with normal glands and areas of complex atypical hyperplasia within the same specimen. The normal glands expressed both of the isoforms at similar levels, whereas there was increased predominance of one isoform in hyperplastic areas and in tumors, which suggested that the loss of coordinated expression of PR isoforms was an early event in tumor p rogression. The majority of tumors [27 (58%) of 46] expressed only one PR i soform, and the proportion expressing either PRA or B was the same [14 (30% ) of 46, and 13 (28%) of 46, respectively]. One-half of all tumors ([23 (50 %) of 46] expressed either PRA only or a predominance of PRA, and a few tum ors [10 (22%) of 46] expressed comparable levels of PRA and B, Similar Leve ls of PRA and B were noted only in FIGO grade 1 tumors, whereas higher grad es (2 and 3) were associated with a predominance of one isoform. In summary , expression of only one PR isoform was common in endometrial cancers, whic h indicates that the decreased PR levels observed in these cancers arise fr om the loss of one PR isoform. Expression of a single PR isoform was associ ated with higher clinical grade, which suggests a relationship between the loss of PR isoform expression and features of poorer prognosis. Disruption of relative PR isoform expression was observed in complex atypical hyperpla sia, which suggests that early alterations in the ratio of PRA:PRB may prec ede and/or be implicated in the development of endometrial adenocarcinoma, Alterations in the ratio of PR isoform expression are likely to cause disor dered regulation of target genes, resulting in altered progestin action in the uterus, and this may be involved in the pathogenesis of endometrial can cer.