Blockade of transforming growth factor-beta signaling does not abrogate antiestrogen-induced growth inhibition of human breast carcinoma cells

We have studied the role of autocrine transforming growth factor-beta (TGF-beta) signaling on antiestrogen mediated growth inhibition of hormone-dependent T47D and MCF-7 human breast carcinoma cells, Tamoxifen treatment increased the secretion of TGF-beta activity into serum-free cell medium and the cellular content of affinity cross-linked type I and III TGF-beta receptors in both cell lines, Anti-pan-TGF-beta antibodies did not block antiestrogen-induced recruitment in G(1) and inhibition of anchorage-dependent and -independent growth of both cell lines, Early passage MCF-7 cells, which exhibit de detectable type II TGF-beta receptors at the cell surface and exquisite sensitivity to exogenous TGF-beta 1, were transfected with a tetracycline-controllable dominant-negative TGF-beta RII (Delta RII) construct, Although the TGF-beta 1 response was blocked by removal of tetracycline in MCF-7/Delta RII cells, tamoxifen-mediated suppression of Rb phosphorylation, recruitment in G(1), and inhibition of cell proliferation were identical in the presence and absence of tetracycline. TGF-beta 1 treatment up-regulated the Cdk inhibitor p21 and induced its association with Cdk2 in MCF-7 cells; these responses were blocked by the Delta RII transgene product, In MCF-7 cells with a functional TGF-P signaling pathway, tamoxifen did not upregulate p21 nor did it induce association of p21 with Cdk2, suggesting alternative mechanisms for antiestrogen-mediated cytostasis, Finally, transfection of late-passage, TGF-beta 1 unresponsive MCF-7 cells with high levels of TGF-beta RII restored TGF-beta 1-induced growth inhibition but did not enhance tamoxifen response in culture, Taken together these data strongly argue against any role for TGF-beta signaling on tamoxifen-mediated growth inhibition of hormone-dependent breast cancer cells.