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Effects of a Pure Antiestrogen on Apoptosis and Proliferation within Human Breast Ductal Carcinoma in Situ¹

University Departments of Surgery [A. G., P. A. H., N. J. B.] and Pathology [W. F. K.], University Hospital of South Manchester, Manchester M20 2LR, and Department of Epithelial Biology, Cancer Research Campaign Paterson Institute for Cancer Research, Christie Hospital, Manchester M20 4BX [C. S. P.], United Kingdom

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 2 x 2 x 1-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 17ß-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 17ß-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 17ß-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.

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