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

Katri M. Koli, Timothy T. Ramsey, Yong Ko, Teresa C. Dugger, Michael G. Brattain, Carlos L. Arteaga

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

We have studied the role of autocrine transforming growth factor-β (TGF-β) signaling on antiestrogen-mediated growth inhibition of hormone- dependent T47D and MCF-7 human breast carcinoma cells. Tamoxifen treatment increased the secretion of TGF-β activity into serum-free cell medium and the cellular content of affinity cross-linked type I and III TGF-β receptors in both cell lines. Anti-pan-TGF-β antibodies did not block anti-estrogen- induced recruitment in G1 and inhibition of anchorage-dependent and - independent growth of both cell lines. Early passage MCF-7 cells, which exhibit detectable type II TGF-β receptors at the cell surface and exquisite sensitivity to exogenous TGF-β1, were transfected with a tetracycline- controllable dominant-negative TGF-βRII (ΔRII) construct. Although the TGF- β1 response was blocked by removal of tetracycline in MCF-7/ΔRII cells, tamoxifen-mediated suppression of Rb phosphorylation, recruitment in G1, and inhibition of cell proliferation were identical in the presence and absence of tetracycline. TGF-β1 treatment up-regulated the Cdk inhibitor p21 and induced its association with Cdk2 in MCF-7 cells; these responses were blocked by the ΔRII transgene product. In MCF-7 cells with a functional TGF- β signaling pathway, tamoxifen did not up-regulate p21 nor did it induce association of p21 with Cdk2, suggesting alternative mechanisms for antiestrogen-mediated cytostasis. Finally, transfection of late-passage, TGF- β1 unresponsive MCF-7 cells with high levels of TGF-βRII restored TGF-β1- induced growth inhibition but did not enhance tamoxifen response in culture. Taken together these data strongly argue against any role for TGF-β signaling on tamoxifen-mediated growth inhibition of hormone-dependent breast cancer cells.

Original languageEnglish (US)
Pages (from-to)8296-8302
Number of pages7
JournalJournal of Biological Chemistry
Volume272
Issue number13
DOIs
Publication statusPublished - Mar 28 1997

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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