Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors

The role of estrogen as a promoter agent of sporadic breast cancer has been considered by assaying, in benign breast disease (BBD) and in situ carcino mas (CIS), 2 markers, the estrogen receptor alpha (ER alpha) and cathepsin D (cath-D) involved in estrogen action on mammary tissue. ER alpha and cath -D were assayed by quantitative immunohistochemistry using an image analyze r in 170 lesions of varying histological risk (94 BED and 76 CIS), and in " normal" glands close to these lesions. The ER alpha level increased signifi cantly in proliferative BED with atypia (P < .001), in non-high-grade CIS ( P < .001), and in adjacent "normal" glands. ER alpha level was decreased in high-grade ductal CIS (DCIS) and also in adjacent "normal" glands. Cath-D level increased in ductal proliferative BED (P less than or equal to .01) a nd in high-grade DCIS (P less than or equal to .003), but not in the other lesions. After menopause, ER alpha level was increased (P = .012)but not ca th-D level. According to Mac Neman test, the high-grade DCIS were predomina ntly ER alpha negative and cath-D positive (P = .0017), and the other CIS w ere predominantly ER alpha positive and cath-D negative (P = .0002). The 2 markers are overexpressed early in premalignant lesions, but independently. This dissociation suggests a branched model of mammary carcinogenesis invo lving 1 estrogen-independent pathway with high cath-D and low ER alpha leve ls (including high-grade DCIS) and 1 estrogen-dependent pathway, with high ER alpha level (including proliferative BED with atypia and low-grade DCIS) . We propose that ER alpha-negative breast cancers may develop directly fro m high-grade DCIS and that ER alpha assay in preinvasive lesions should be considered in prevention trials with antiestrogens. Copyright (C) 2000 by W .B. Saunders Company.