Gandhi A, Holland P A, Knox W F, Potten C S, Bundred N J
University Department of Surgery, University Hospital of South Manchester, Manchester, United Kingdom.
Cancer Res. 2000 Aug 1;60(15):4284-8.
Adjuvant antiestrogen (AE) therapy has been proposed for all women with ductal carcinoma in situ (DCIS). However, many cases of DCIS are of the high-grade, estrogen receptor (ER)-negative subtype that are unlikely to respond to AE treatment. Hormonal agents work by increasing apoptosis and/or decreasing cell proliferation; therefore, we studied the effect of a pure AE on levels of apoptosis and proliferation in human DCIS xenografts using an in vivo model. Women (n = 23) with mammographic microcalcification suggestive of DCIS were identified at the time of surgery (day 0), a sample of representative tissue was obtained, divided into multiple 2x2x1-mm xenografts, and implanted s.c. into female BALB/c nu/nu mice (eight xenografts/mouse). Day 0 grafts underwent immunohistochemical assessment of ER status. Fourteen days after implantation, four xenografts were retrieved and mice were randomly divided into one of three treatment groups: (a) insertion of a slow release 2-mg 17beta-estradiol pellet; (b) weekly 5-mg injections of the pure AE Faslodex (Zeneca Pharmaceuticals); and (c) injections of a control vehicle oil alone. After 2 weeks of treatment, the remaining four xenografts were retrieved from each mouse. Retrieved xenografts containing DCIS were assessed for morphological evidence of apoptotic cell death [apoptotic index (AI)] and cell proliferation (by immunohistochemical detection of the Ki67 proliferation antigen LI). Both AI and LI were higher in the day 0 specimens of 16 ER- DCIS lesions compared with 7 ER+ DCIS lesions (mean values, 1.47% versus 0.32% and 20.6% versus 3.1%; both P<0.0001). AI and LI values within ER- DCIS did not differ between xenografts exposed to 17beta-estradiol or AE treatment compared with the controls or pretreatment values (mean AI and LI in estradiol-treated, antiestrogen-treated, and control groups 1.04% versus 0.98% versus 1.29% and 17.2% versus 20.5% versus 17.7% respectively). In contrast, treatment of mice bearing ER+ DCIS xenografts with 17beta-estradiol raised both the AI (1.03% versus 0.40%, P = 0.03) and LI (11.0% versus 5.1%, P = 0.007) compared with controls. AE therapy of ER+ DCIS xenografts did not affect proliferation but resulted in higher apoptosis than in controls (0.9% versus 0.4% respectively, P = 0.04). AE therapy should be reserved for patients with estrogen receptor positive DCIS.
辅助抗雌激素（AE）疗法已被推荐用于所有导管原位癌（DCIS）女性患者。然而，许多DCIS病例属于高级别、雌激素受体（ER）阴性亚型，不太可能对AE治疗产生反应。激素药物通过增加细胞凋亡和/或减少细胞增殖发挥作用；因此，我们使用体内模型研究了一种纯AE对人DCIS异种移植瘤中细胞凋亡和增殖水平的影响。在手术时（第0天）确定了23名有乳腺钼靶微钙化提示DCIS的女性，获取代表性组织样本，将其分成多个2×2×1毫米的异种移植瘤，然后皮下植入雌性BALB/c nu/nu小鼠（每只小鼠植入8个异种移植瘤）。对第0天的移植瘤进行ER状态的免疫组织化学评估。植入后14天，取出4个异种移植瘤，将小鼠随机分为三个治疗组之一：（a）植入一个2毫克的缓释17β-雌二醇药丸；（b）每周注射5毫克纯AE氟维司群（阿斯利康制药公司）；（c）仅注射对照赋形剂油。治疗2周后，从每只小鼠身上取出剩余的4个异种移植瘤。对含有DCIS的取出异种移植瘤进行凋亡细胞死亡的形态学证据[凋亡指数（AI）]和细胞增殖评估（通过免疫组织化学检测Ki67增殖抗原LI）。与7个ER+ DCIS病变的第0天标本相比，16个ER- DCIS病变的第0天标本中的AI和LI均更高（平均值分别为%1.47对0.32%和20.6%对3.1%；P均<0.0001）。与对照组或预处理值相比，暴露于17β-雌二醇或AE治疗的ER- DCIS异种移植瘤中的AI和LI值没有差异（雌二醇治疗组、抗雌激素治疗组和对照组的平均AI和LI分别为1.04%对0.98%对1.29%和17.2%对20.5%对17.7%）。相比之下，与对照组相比，用17β-雌二醇治疗携带ER+ DCIS异种移植瘤的小鼠可提高AI（1.03%对0.40%，P = 0.03）和LI（11.0%对5.1%，P = 0.007）。ER+ DCIS异种移植瘤的AE治疗不影响增殖，但导致凋亡高于对照组（分别为0.9%对0.4%，P = 0.04）。AE疗法应仅用于雌激素受体阳性的DCIS患者。
