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₁-Antitrypsin Blocks the Release of Transforming Growth Factor- from MCF-7 Human Breast Cancer Cells¹

Department of Biology, Rider University (J.Y., A.T.), Lawrenceville, New Jersey 08648; and the Department of Obstetrics and Gynecology (S.S.K., J.K., T.H.F.) and the Kaplan Cancer Center (T.H.F.), New York University Medical Center, New York, New York 10016

Address all correspondence and requests for reprints to: Thomas H. Finlay, Ph.D., New York University Medical Center, 550 First Avenue, New York, New York 10016.

Human breast cancer cells synthesize and release a variety of growth-modulating substances in response to estrogen stimulation, and it is generally accepted that the growth-promoting effects of estrogens are due at least in part to this autocrine/paracrine mechanism. Several of these growth-modulating substances, including transforming growth factor- (TGF) and its analogs, have been shown to require pericellular proteolysis for activation or release. Recently, we reported that MCF-7 human breast cancer cells are able to synthesize ₁-antitrypsin (₁-AT), the major elastase inhibitor in human serum, and that there is a negative correlation between anchorage-independent growth of MCF-7 cells in soft agar and synthesis of ₁-AT. The studies we present here were undertaken to gain an understanding of the mechanisms responsible for this observation. We show that release of TGF from its membrane-bound precursor on MCF-7 cells is blocked by ₁-AT whether the cells were maintained in the presence or absence of estradiol and that there is a clear dose-response relationship between the ₁-AT concentration and both the release of TGF and growth in soft agar. Consistent with this, TGF release was increased in the presence of antibody to ₁-AT. In contrast, TGF release and growth in soft agar were not blocked by peptide inhibitors specific for trypsin- or chymotrypsin-like enzymes. The ₁-AT concentration required for a half-maximal effect is lower for inhibition of TGF release than it is for inhibition of colony formation (0.4 vs.1.5 µmol/L). However, both values are in the range of concentrations one might expect at the cell surface in vivo. A new MCF-7 cell subline producing 10-fold higher levels of ₁-AT than its parent cell line was constructed by stable transfection of MCF-7 ML cells (a subline producing low levels of ₁-AT) with an ₁-AT complementary DNA. Growth in soft agar and release of TGF were significantly decreased in cells transfected with the ₁-AT complementary DNA compared to those in cells transfected with vector alone, although, TGF expression was the same. The above observations support a model for growth regulation in human breast ductal epithelial cells in which growth factor activation and release are dependent on the coordinate action of proteases and protease inhibitors. This model would predict that ₁-AT can act as a tumor suppressor in inhibiting the growth of breast cancer cells.

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