Arnett-Mansfield R L, deFazio A, Wain G V, Jaworski R C, Byth K, Mote P A, Clarke C L
Westmead Institute for Cancer Research, Westmead Hospital, Westmead, New South Wales 2145, Australia.
Cancer Res. 2001 Jun 1;61(11):4576-82.
The nuclear receptor for the female hormone progesterone (PR) is widely expressed in uterine cancer. PR is expressed as two proteins (PRA and PRB) with different functions, and in vitro evidence reveals PRA to inhibit PRB function, so the cellular ratio of PRA:PRB is likely to be an important determinant of progesterone action. The relative expression of PRA and B and their involvement in the pathogenesis of endometrial cancer is not known. The aims of this study were to determine PRA and B expression by dual immunofluorescent histochemistry in endometrial adenocarcinomas compared with expression in normal and hyperplastic glands, and to correlate expression in tumors with clinical features including grade. Significantly lower PR levels were 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 progression. The majority of tumors [27 (58%) of 46] expressed only one PR isoform, 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 tumors [10 (22%) of 46] expressed comparable levels of PRA and B. Similar levels of PRA and B were noted only in FIGO grade 1 tumors, whereas higher grades (2 and 3) were associated with a predominance of one isoform. In summary, expression of only one PR isoform was common in endometrial cancers, which indicates that the decreased PR levels observed in these cancers arise from the loss of one PR isoform. Expression of a single PR isoform was associated 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 hyperplasia, which suggests that early alterations in the ratio of PRA:PRB may precede and/or be implicated in the development of endometrial adenocarcinoma. Alterations in the ratio of PR isoform expression are likely to cause disordered regulation of target genes, resulting in altered progestin action in the uterus, and this may be involved in the pathogenesis of endometrial cancer.
女性激素孕酮的核受体（PR）在子宫癌中广泛表达。PR以两种功能不同的蛋白（PRA和PRB）形式表达，体外证据显示PRA可抑制PRB的功能，因此PRA与PRB的细胞比例可能是孕酮作用的重要决定因素。PRA和PRB的相对表达及其在子宫内膜癌发病机制中的作用尚不清楚。本研究的目的是通过双重免疫荧光组织化学法确定子宫内膜腺癌中PRA和PRB的表达，并与正常及增生腺体中的表达进行比较，同时将肿瘤中的表达与包括分级在内的临床特征相关联。与同一标本中的正常腺体和复杂性非典型增生区域相比，肿瘤中的PR水平显著降低。正常腺体中两种异构体的表达水平相似，而在增生区域和肿瘤中一种异构体的优势增加，这表明PR异构体协调表达的丧失是肿瘤进展中的早期事件。大多数肿瘤[46例中的27例（58%）]仅表达一种PR异构体，表达PRA或PRB的比例相同[分别为46例中的14例（30%）和46例中的13例（28%）]。所有肿瘤的一半[46例中的23例（50%）]仅表达PRA或PRA占优势，少数肿瘤[46例中的10例（22%）]表达的PRA和PRB水平相当。仅在国际妇产科联盟（FIGO）1级肿瘤中观察到PRA和PRB水平相似，而较高分级（2级和3级）与一种异构体占优势相关。总之，仅表达一种PR异构体在子宫内膜癌中很常见，这表明在这些癌症中观察到的PR水平降低是由于一种PR异构体的缺失所致。单一PR异构体的表达与较高的临床分级相关，这表明PR异构体表达的丧失与预后较差的特征之间存在关联。在复杂性非典型增生中观察到PR异构体相对表达的破坏，这表明PRA与PRB比例的早期改变可能先于子宫内膜腺癌的发生和/或与之相关。PR异构体表达比例的改变可能导致靶基因调控紊乱，从而导致子宫中孕激素作用改变，这可能参与子宫内膜癌的发病机制。
