Roger P, Daures J P, Maudelonde T, Pignodel C, Gleizes M, Chapelle J, Marty-Double C, Baldet P, Mares P, Laffargue F, Rochefort H
Unité Hormones et Cancer (U 148) Inserm, Montpellier, France.
Hum Pathol. 2000 May;31(5):593-600. doi: 10.1053/hp.2000.6687.
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.
通过在良性乳腺疾病（BBD）和原位癌（CIS）中检测两种参与雌激素对乳腺组织作用的标志物——雌激素受体α（ERα）和组织蛋白酶D（cath-D），来探讨雌激素作为散发性乳腺癌促发因素的作用。使用图像分析仪通过定量免疫组织化学方法对170个具有不同组织学风险的病变（94个BBD和76个CIS）以及这些病变附近的“正常”腺体进行ERα和cath-D检测。在伴有非典型增生的增殖性BBD（P <.001）、非高级别CIS（P <.001）以及相邻的“正常”腺体中，ERα水平显著升高。在高级别导管原位癌（DCIS）以及相邻的“正常”腺体中，ERα水平降低。Cath-D水平在导管增殖性BBD（P ≤.01）和高级别DCIS（P ≤.003）中升高，但在其他病变中未升高。绝经后，ERα水平升高（P =.012），但cath-D水平未升高。根据麦克内曼检验，高级别DCIS主要为ERα阴性和cath-D阳性（P =.0017），其他CIS主要为ERα阳性和cath-D阴性（P =.0002）。这两种标志物在癌前病变早期均有过度表达，但相互独立。这种分离提示乳腺致癌的分支模型，涉及一条cath-D水平高而ERα水平低的雌激素非依赖途径（包括高级别DCIS）和一条ERα水平高的雌激素依赖途径（包括伴有非典型增生的增殖性BBD和低级别DCIS）。我们提出ERα阴性乳腺癌可能直接由高级别DCIS发展而来，并且在抗雌激素预防试验中应考虑对浸润前病变进行ERα检测。
