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
carcinomas (CIS), 2 markers, the
estrogen receptor alpha (
ERalpha) and
cathepsin D (cath-D) involved in
estrogen action on mammary tissue.
ERalpha and cath-D were assayed by quantitative immunohistochemistry using an image analyzer in 170 lesions of varying histological risk (94 BBD and 76 CIS), and in "normal" glands close to these lesions. The
ERalpha level increased significantly in proliferative BBD with atypia (P < .001), in non-high-grade CIS (P < .001), and in adjacent "normal" glands.
ERalpha level was decreased in high-grade ductal CIS (
DCIS) and also in adjacent "normal" glands. Cath-D level increased in ductal proliferative BBD (P < or = .01) and in high-grade
DCIS (P < or = .003), but not in the other lesions. After menopause,
ERalpha level was increased (P = .012) but not cath-D level. According to Mac Neman test, the high-grade
DCIS were predominantly
ERalpha negative and cath-D positive (P = .0017), and the other CIS were predominantly
ERalpha 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 involving 1
estrogen-independent pathway with high cath-D and low
ERalpha levels (including high-grade
DCIS) and 1
estrogen-dependent pathway, with high
ERalpha level (including proliferative BBD with atypia and low-grade
DCIS). We propose that
ERalpha-negative breast
cancers may develop directly from high-grade
DCIS and that
ERalpha assay in preinvasive lesions should be considered in prevention trials with
antiestrogens.