Effect of tamoxifen on mammary preneoplasia: relevance to chemopreventive intervention.

The nonsteroidal antiestrogen tamoxifen (TAM) is used to treat receptor-positive breast cancer and is now being evaluated for prophylaxis of "high-risk" population. The present study seeks to examine mechanisms that may be critical for prophylactic effects of TAM on transformation-sensitive mammary tissue. The experimental systems utilized included: in vivo rodent models for mammary tumorigenesis and in vitro cell culture models for preneoplastic transformation. In the in vivo models TAM suppressed constitutive, as well as carcinogen-induced proliferation, expression of mammary tumor virus-associated reverse transcriptase activity and decreased the incidence and frequency of mammary hyperplastic alveolar nodules. In the in vitro models TAM suppressed carcinogen-induced DNA damage, altered cellular metabolism of estradiol favoring the formation of less estrogenic catechols, and down-regulated anchorage-independent growth that is induced by ras oncogene and chemical carcinogen. Effective down-regulation of specific proliferative and metabolic biomarkers that are perturbed in mammary cell prior to tumorigenesis provides evidence that altered cellular metabolism of E2 may, in part, be responsible for antiproliferative and prophylactic properties of TAM against mammary tumorigenesis.