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Distinct Tumor Stage–Specific Inhibitory Effects of 2-Methoxyestradiol in a Breast Cancer Mouse Model Associated with Id-1 Expression

Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Jeffrey E. Green, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, NIH, Room C629, Building 41, 41 Medlars Drive, Bethesda, MD 20892. Phone: 301-435-5193; Fax: 301-496-8395; E-mail: jegreen{at}nih.gov.

2-Methoxyestradiol (2ME₂), a metabolite of 17-ß-estradiol, inhibits angiogenesis and has additional antitumor activities. We have analyzed the tumor stage–specific effects of 2ME₂ in the C3(1)/Tag transgenic mouse model for breast cancer, which spontaneously develops estrogen receptor–negative mammary tumors following a predictable progression of lesion formation. When given either as a therapeutic agent in established tumors (late intervention study) or in mice with pre-invasive mammary lesions (early intervention study), tumor growth was reduced by 60% compared with untreated controls and was associated with an induction of apoptosis. In a prevention study, a significant reduction in mammary intraepithelial neoplasia (MIN) lesions was observed in animals beginning treatment at 6 weeks of age, before the appearance of histopathologic abnormalities. However, although 2ME₂ reduced the number of MIN lesions in the prevention study, a paradoxical increase in tumor multiplicity and growth rate was observed. This was associated with unusual cystic tumor formation, in which significant central necrosis was observed, surrounded by an outer region of proliferative tumor cell growth. The characteristics of the cystic tumor formation in mice treated with 2ME₂ at early ages are consistent with an impaired angiogenic response as observed in mice deficient for inhibitor of differentiation (Id-1). We further show that Id-1 expression is negatively regulated by 2ME₂, which may be an additional mechanism for the antiangiogenic effect of 2ME₂. Although 2ME₂ significantly reduced tumor growth at late stages, these results also suggest that altered tumor morphology and accelerated tumor growth may occur if 2ME₂ is administered in a prevention setting for prolonged periods. (Cancer Res 2006; 66(7): 3495-503)

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