Progesterone receptor (PR) mediates the effects of progesterone in mammary tissues and plays a crucial role in normal breast development and in breast cancer. PR proteins are expressed as two isoforms, PRA and PRB, that have different capacities to activate target genes, yet it is unknown whether progesterone action in normal and malignant breast is mediated by PRA and/or PRB. This study determines the relative expression of PRA and PRB in normal breast and in benign, premalignant and malignant archival breast lesions by dual immunofluorescent histochemistry. In normal breast and in proliferative disease without atypia (PDWA) PRA and PRB were co-expressed within the same cells in comparable amounts, implicating both isoforms in progesterone action. In atypical lesions, however, there was a significant increase in predominant expression of PRA or PRB, with lesion progression from the normal state to malignancy. PR isoform predominance, especially PRA predominance, was evident in a high proportion of ductal carcinomas in situ (DCIS) and invasive breast lesions. In the normal breast and in PDWA, the relative expression of PRA and PRB in adjacent cells was homogenous. There was a significant increase in cell-to-cell heterogeneity of PR isoform expression in ADH and DCIS lesions and in the majority of breast cancers. Heterogeneous cell-to-cell expression of PR isoforms occurred prior to overall predominant expression of one isoform in premalignant breast lesions, demonstrating that loss of control of relative PRA:PRB expression is an early event in the development of breast cancer. PRA:PRB ratios within a breast lesion are likely to be important as both markers and effectors of tumor growth and development, and progressively aberrant PR isoform expression may play a role in the etiology of breast cancer.

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A forensic autopsy series of 519 women more than 14 years old was studied for prevalence of benign, atypical, and occult malignant breast lesions. The women included Anglos (non-Hispanic whites), Hispanics, and American Indians from New Mexico and Eastern Arizona. These three ethnic/racial groups are at markedly different risk for the development of breast cancer (Anglo 89 of 100,000 women per year, Hispanic 45.5, and American Indian 24.9. There were striking ethnic/racial and age-related differences in both the prevalence and magnitude of all forms of nonproliferative and proliferative fibrocystic disease. The various subsets of fibrocystic disease were highly associated with each other. Such lesions as apocrine metaplasia, sclerosing adenosis, and lobular microcalcification showed as much difference according to ethnic/racial background and age as the more common cystic change and duct epithelial hyperplasia. Atypical lobular and ductal hyperplasia, carcinoma in situ, and occult invasive carcinoma were uncommon and also occurred in ethnic/racial groups in a pattern that parallels the cancer risk in those groups.Cancer 60:2751-2760, 1987. HE GEOGRAPHIC AREA of New Mexico and EasternT Arizona is populated by three distinct ethnic/racia1 groups. Of these groups, the Anglo women (nonHispanic white) are at high risk for breast carcinoma with an incidence rate of 89 per 100,000 women per year; the American Indian women are at low risk (24.9 per 100,000 women per year); and the Accepted for publication June 8, 1987. which include epithelial proliferation in the lobular unit, have been considered to be more significant in terms of breast cancer risk than nonproliferative It was hypothesized that morphologic lesions of possible significance in the etiology of carcinoma would show a distribution similar to that of the risk for breast cancer in the three populations. Methods and MaterialsA series of 5 19 women older than 14 years autopsied by the New Mexico Office of the Medical Investigator was included in this study. With the exception of cases in which tissue was traumatically destroyed or decomposed, and rare instances in which all tissue had to be returned to the body, the cases were unselected, consecutive autopsies performed between December 1978 and December 1983. The series included 229 Caucasian, 156 Hispanic, and 134 American Indian women. The age range was from 15 to 98 years. No women with clinically apparent breast carcinomas were included in the series. Twenty-nine women were pregnant or immediately postpartum. These women were not included in the statistical analysis for fibrocystic change because fibrocystic features could be obscured by pregnancy-asso-275 1

Introduction Increased mammographic density is a strong risk factor for breast cancer. The reasons for this are not clear; two obvious possibilities are increased epithelial cell proliferation in mammographically dense areas and increased breast epithelium in women with mammographically dense breasts. We addressed this question by studying the number of epithelial cells in terminal duct lobular units (TDLUs) and in ducts, and their proliferation rates, as they related to local breast densities defined histologically within individual women.

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