POSTTRANSCRIPTIONAL REGULATION OF TRANSFORMING GROWTH FACTOR-BETA 1

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In many cell types there is a large discrepancy between the measured levels of TGF-Beta 1 mRNA and protein. Furthermore, many members of the steroid hormone superfamily, including the clinically significant antiestrogens and certain novel synthetic progestins, appear to increase TGF-Beta 1 protein production without any concomitant change in mRNA levels. This suggests that translational or post-translational mechanisms may play an important role in the regulation of TGF-Beta 1 production. We have performed polysome analyses on a number of cell types and have shown that both the initial recruitment and subsequent translation of the TGF- Beta 1 mRNA may be inefficient. In certain cells such as the breast adenocarcinoma line MCF-7, there is evidence that a low abundance of small TGF-Beta 1 mRNA transcript may be preferentially translated. To investigate these phenomena further, expression constructs have been made in which various portions of the 5' and 3' UTRs of the TGF-Beta 1 cDNA have been deleted. These constructs are being used for in vitro transcription/translation and in the generation of stable trans- fectants, in order to identify regions of the TGF-Beta 1 mRNA that are responsible for the translational regulation, particularly in response to steroid hormone superfamily members. Preliminary experiments indicate that the 3' UTR may be critical for efficient mRNA translation. The production of TGF-Beta 1 by cell lines in vitro in response to steroid hormones varies dramatically with culture conditions. The methodology is being developed to allow measurement of circulating TGF-Betas in the plasma of human subjects with breast cancer, before and after treatment with the antiestrogen tamoxifen and a synthetic retinoid, to determine whether TGF- Betas are induced by these agents in vivo as well as in vitro. An understanding of the mechanisms whereby steroids and related compounds regulate the production 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.