Transforming growth factors type β1 and β2 are equipotent growth inhibitors of human breast cancer cell lines

Abstract

At least one member of the TGF-β family, TGF-β1, has been previously shown to inhibit the anchorage-independent growth of some human breast cancer cell lines (Knabbe et al., 1987; Arteaga et al., 1988). Members of the TGF-β family might, therefore, provide new strategies for breast cancer therapy. We have studied the inhibitory effects of TGF-β1 and TGF-β2 on the anchorage-independent growth of the estrogen receptor-negative cell lines MDA-MB-231, SK-BR-3, Hs578T, MDA-MB-468, and MDA-MB-468-S4 (an MDA-MB-468 clone not growth inhibited by EGF) and the estrogen receptor-positive cell lines MCF7, ZR-75-1, T-47D. TGF-β1 and TGF-β2 caused a 75–90% growth inhibition of MDA-MB-231, SK-BR-3, Hs578T, and MDA-MB-468 cells and a 50% growth inhibition of ZR-75-1 and early passage (< 100) MCF7 cells. T-47D cells responded to TGF-β only in serum-free conditions in the presence of IGF-1 or EGF. The growth of MDA-MB-468-S4 cells and late passage (> 500) MCF7 cells was not inhibited by TGF-β1 or TGF-β2. TGF-β-sensitive MCF7 and MDA-MB-231 cells did not respond to Muellerian inhibiting substance (MIS), a TGF-β-related polypeptide. TGF-β1 and TGF-β2 were mutually competitive for receptor binding with a similar affinity (Kd 25-130 pM, 1,000-13,000 sites per cell). To determine the time course of the TGF-β effect, an anchorage-dependent growth assay was carried out using MDA-MB-231 cells. Growth inhibition occurred at 6 days, and cell-cycle changes were seen 12 hr after the addition of TGF-β. Cells accumulated in the G1 phase and were thus inhibited from entering the S-phase. These data indicate that TGF-β is a potent growth inhibitor in most breast cancer cell lines and provide a basis for studying TGF-β effects in vivo.