REGULATION OF THE TGF BETA SYSTEM BY ANTIESTROGENS AND RETINOIDS

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Clinically important antiestrogens, such as tamoxifen, have been shown to regulate transforming growth factor-beta1 (TGF-beta1) expression in human breast tumor stroma in vivo. In vitro experiments suggest this regulation is post- transcriptional. To analyze a possible translational component, we have recharacterized the start sites for the TGF-beta1 mRNAs, and by deletion analysis we have shown that the 5'UTR contains multiple embedded cis-regulatory elements, and that the open reading frame contains a novel inhibitory element. Selection of different start sites determines whether stimulatory or inhibitory elements dominate. A gross map of the cis elements has been constructed, and these elements have been shown to be active both in vitro and in vivo. The longest (2.5kb) and shortest (1.4kb) TGF-beta1 transcripts are poorly translated, while the 1.9kb transcript is very efficiently translated. Immunohistochemical techniques were used to determine TGF-beta isoform levels in patients with advanced metastatic breast cancer, before and after treatment with the antiestrogen tamoxifen and a synthetic retinoid. No changes in TGF-beta1 levels were observed in skin biopsies of these women following treatment, although there was a trend towards increased TGF-beta2 levels in the epidermis. Similarly, no changes in circulating TGF-beta1 levels in the plasma were observed in this patient cohort. Currently the analysis is being extended to sera and stereotactically guided core biopsies of tamoxifen-naive women at high risk for developing breast cancer, or with newly diagnosed disease. A similar immunohistochemical analysis is being performed using Sprague-Dawley rats initiated with the mammary carcinogen N-methyl-nitrosourea and treated with various combinations of antiestrogens and synthetic retinoids. This animal model work should complement and guide the patient studies. An understanding of the mechanisms whereby steroids and related compounds regulate the production and activity of the TGF-beta family of growth inhibitors may allow the rational design of more potent pharmacological agents for use in chemoprevention or chemotherapy of cancer.