Recently it has been shown that epithelial cell expression of the estrogen receptor (ER) and that of the proliferation-associated marker Ki-67 are almost mutually exclusive in the normal premenopausal human breast but that coexpression frequently occurs in estrogen receptor-positive (ER؉) breast cancers. This coexpression may indicate disordered expression of ER in the cell cycle or failure to suppress division of ER؉ cells and could be important in neoplastic transformation. The purpose of this study was to determine whether in situ proliferations known to be associated with different levels of risk for developing breast cancer contain these coexpressing cells and, if so, the stage at which they occur. We found that ER؉ proliferating cells were rare in premenopausal lobules but increased with age in the normal breast. There was no difference in nonlesional tissue between cancerous and noncancerous breasts. The percentage of dual-expressing cells was significantly increased , however , in all of the in situ proliferations and correlated positively with the level of risk of developing breast cancer. We suggest that development of at least some human breast cancers is associated with increasing failure to down-regulate ER as Estrogen is thought to be important in the pathogenesis of breast cancer and is associated with most of the epidemiological risk factors associated with the disease. 1 Furthermore, the antiestrogen tamoxifen decreases proliferation in breast cancers, 2,3 although its role in preventing the disease is in dispute at present. 4 Estrogen is also associated with epithelial proliferation in the noncancerous breast during the menstrual cycle 5,6 and in pregnancy 7 and acts on cells via the estrogen receptor (ER). Recently Clarke 8 has shown that there is almost mutual exclusion of steroid receptor expression and cell proliferation in normal human breast tissue, judged by the lack of dual immunostaining for ER and the human Ki-67 proliferation-associated nuclear antigen, which is usually demonstrable in the late G1, S, G2, and M phases of the cell cycle. This relationship, however, is lost in some breast cancers, in which a variable percentage of proliferating cells are estrogen receptor positive (ERϩ). This coexpression may therefore indicate disordered control of cell division in ERϩ cells or disordered regulation of ER in dividing cells and could represent an important pathogenetic step in the development of breast cancer. We have previously shown that the percentage of ERϩ cells within precancerous lesions correlates with the risk attributed to them in prospective studies. 9 Furthermore, a fundamental change appears to occur between hyperplasia of usual type (without atypia, HUT) and atypical ductal hyperplasia (ADH). The percentage of ERϩ cells in the former type of lesion increases with age, as it does in the normal breast, whereas in ADH it is high at all ages, as it is in ERϩ ductal carcinoma in situ (DCIS). This suggests that regulation of ER expression or control of numbers of ERϩ cells esca...

As oestrogen is associated with most of the epidemiological risk factors for breast cancer, the number and distribution of oestrogen receptor positive (ER+) cells could have a bearing on the development of the disease. ER+ cells were thus studied in the normal breast and in the spectrum of in situ proliferations which range from non‐atypical hyperplasia to in situ carcinoma and are associated with different levels of risk for developing breast cancer. In the normal pre‐menopausal breast, ER+ cells comprised the minority and were distributed singly, being surrounded by oestrogen receptor negative (ER−) cells. ER+ cells showed a statistically significant increase with age, reaching a plateau after the menopause, and the increase was associated with a tendency for positive cells to become contiguous in patches of variable size. A small proportion of lobules showing involutional change comprised over 90 per cent ER+ cells. The significance of this feature is not clear but no evidence was found that it was pre‐cancerous. The percentage of ER+ cells was slightly increased in hyperplasia of usual type (non‐atypical hyperplasia, HUT) and the relationship to age was maintained. The staining pattern was variable; in some lesions ER+ cells were surrounded by ER− cells whereas in others there were contiguous groups of positive cells sometimes accounting for more than 90 per cent of cells in the lesion. In contrast, all cases of atypical ductal hyperplasia (ADH), lobular in situ neoplasia (LIN) and ductal carcinoma in situ (DCIS) exhibited positivity of contiguous cells accounting for the majority in the lesions. Furthermore, the relationship between ER+ cell numbers and age was lost in these lesions, indicating autonomy of ER expression or of proliferation of cells expressing the receptor. It is hypothesized that this dysregulation of receptor expression or of ER+ cell numbers at the ADH stage may be the precursor of abnormal expression of cyclins and other cell cycle control proteins which have been shown first to appear in DCIS. Copyright © 1999 John Wiley & Sons, Ltd.

The hypothetical multistep model of carcinogenesis indicates that breast cancer develops via a series of intermediate hyperplastic lesions through in situ to invasive carcinoma. To identify the risk inherent within the different morphologic lesions, we have analyzed the data from 674 benign biopsy specimens comprising 120 cases who subsequently developed breast cancer and 382 controls (matched for age and date of biopsy) spanning a period up to 20 years of follow-up (mean 66.95 months). In this series we have confirmed an increased risk associated with certain types of benign breast lesions. Atypical lobular hyperplasia was the most significant risk factor for breast cancer with more unfavorable outcome in patients <50 years of age (p = 0.003) and a relative risk (RR) of 4.55 (confidence interval [CI] 1.77-11.69). Hyperplasia of usual type showed an RR of 1.53 (CL 1.10-2.13) with a statistically worse probability of survival (cancer-free time) for patients >50 years. For atypical ductal hyperplasia the RR was 2.03 (CI 0.80-1.39). Blunt duct adenosis was significantly more common in cases progressing to breast cancer compared with controls, showing an RR of 2.08 (CI 1.12-2.85). We describe in detail the criteria of morphologic changes observed in blunt duct adenosis and define, for the first time, the level of risk associated with each of its six subtypes. Improved knowledge of breast carcinogenesis will provide insight for defining high-risk groups thus resulting in improved screening and management regimens.

Results-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, diVered 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. Conclusion-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. (J Clin Pathol 2000;53:778-783)

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