Shoker B S, Jarvis C, Clarke R B, Anderson E, Munro C, Davies M P, Sibson D R, Sloane J P
Department of Pathology, University of Liverpool, UK.
J Clin Pathol. 2000 Oct;53(10):778-83. doi: 10.1136/jcp.53.10.778.
In normal breast tissue the oestrogen receptor (ER) and the proliferation associated antigen Ki67 are negatively associated, indicating that ER+ cells are non-dividing, or that the receptor is downregulated as cells enter cycle. This relation is completely or partially lost in many ER+ breast cancers and in in situ proliferations associated with an increased cancer risk, where coexpression of the two markers is often found.
To determine whether similar changes can be identified in other risk associated breast lesions.
PATIENTS/METHODS: Paraffin wax blocks from 12 cases of lactational change, 21 apocrine metaplasias, 22 duct ectasias, 20 sclerosing adenosis, 20 fibroadenomas, 19 phyllodes tumours, 20 radial scars, 21 papillomas (15 solitary and six multiple), 15 gynaecomastias, and nine postmortem male breast tissues were retrieved. Immunohistochemistry was used to determine the expression of ER and dual labelling immunofluorescence was used to detect cells expressing both ER and Ki67.
Increased numbers of ER+ cells were seen in sclerosing adenosis, radial scars, papillomas, fibroadenomas, and phyllodes tumours but not in apocrine cysts (where no ER+ cells were detected) or duct ectasia (where normal numbers were found). As in the normal breast, the proportion of ER+ cells increased with age in all lesions with the exception of fibroadenomas. Coexpression of ER and Ki67 was found in an increased proportion of cells of all risk associated lesions studied. ER+ cells were less likely to be dividing than ER- cells in all cases, although this was significant only for sclerosing adenosis. The data on sclerosing adenosis, radial scars, papillomas, and fibroadenomas are comparable with those reported previously in hyperplasia of usual type, whereas those in duct ectasia are similar to those of the normal breast. The findings in all lesions, however, differed from those in ductal carcinoma in situ, where proportions of ER+ and ER+/Ki67+ cells are higher and the relation between ER+ cell numbers and age is lost. Thus, the nature and degree of dysregulation of ER in benign breast lesions is broadly in accordance with the degree of risk of developing breast cancer with which they are associated. In gynaecomastia, the proportions of ER+ and ER+/Ki67+ cells were comparable with those seen in benign female breast lesions, but changes with age were not observed. However, the changes in gynaecomastia were similar to those seen in normal male breast.
These findings are in keeping with the contention that the dissociation of ER and Ki67 expression is a very early change in the pathway to many breast cancers. However, this change might only have preneoplastic importance in the hormonal milieu of the female breast.
在正常乳腺组织中，雌激素受体（ER）与增殖相关抗原Ki67呈负相关，这表明ER阳性细胞不分裂，或者细胞进入细胞周期时该受体表达下调。在许多ER阳性乳腺癌以及与癌症风险增加相关的原位增殖病变中，这种关系完全或部分丧失，常常发现这两种标志物的共表达。
确定在其他与风险相关的乳腺病变中是否能识别出类似变化。
患者/方法：检索了12例哺乳期改变、21例大汗腺化生、22例导管扩张、20例硬化性腺病、20例纤维腺瘤、19例叶状肿瘤、20例放射状瘢痕、21例乳头状瘤（15例单发和6例多发）、15例男性乳腺增生以及9例男性尸检乳腺组织的石蜡块。采用免疫组织化学法测定ER的表达，并采用双重免疫荧光标记法检测同时表达ER和Ki67的细胞。
在硬化性腺病、放射状瘢痕、乳头状瘤、纤维腺瘤和叶状肿瘤中可见ER阳性细胞数量增加，但在大汗腺囊肿（未检测到ER阳性细胞）或导管扩张（ER阳性细胞数量正常）中未发现。与正常乳腺一样，除纤维腺瘤外，所有病变中ER阳性细胞的比例均随年龄增加。在所研究的所有与风险相关的病变中，发现ER和Ki67共表达的细胞比例增加。在所有病例中，ER阳性细胞比ER阴性细胞分裂的可能性小，但仅在硬化性腺病中具有统计学意义。关于硬化性腺病、放射状瘢痕、乳头状瘤和纤维腺瘤的数据与先前报道的普通型增生的数据相当，而导管扩张中的数据与正常乳腺相似。然而，所有病变的结果与导管原位癌不同，导管原位癌中ER阳性和ER/Ki67双阳性细胞的比例更高，且ER阳性细胞数量与年龄之间的关系消失。因此，良性乳腺病变中ER失调的性质和程度与它们所关联的患乳腺癌风险程度大致相符。在男性乳腺增生中，ER阳性和ER/Ki67双阳性细胞的比例与良性女性乳腺病变中的比例相当，但未观察到随年龄的变化。然而，男性乳腺增生中的变化与正常男性乳腺中的变化相似。
这些发现支持以下观点，即ER和Ki67表达的解离是许多乳腺癌发生途径中的一个非常早期的变化。然而，这种变化可能仅在女性乳腺的激素环境中具有癌前意义。
