Blockade of tumor cell transforming growth factor-βs enhances cell cycle progression and sensitizes human breast carcinoma cells to cytotoxic chemotherapy

Tohru Ohmori, Jin Long Yang, James O. Price, Carlos L. Arteaga

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

We have examined the effect of neutralizing TGF-β antibodies on cisplatin-mediated cytotoxicity against MDA-231 human breast tumor cell spheroids. These tridimensional in vitro systems have been shown to recapitulate the drug sensitivity pattern of tumor cells in vivo. MDA-231 tumor cell spheroids exhibit higher protein levels of the cyclin-dependent kinase (Cdk) inhibitors p21 and p27 and >10-fold lower Cdk2 activity compared to adherent cell monolayers, as well as pRb hypophosphorylation, a predominant G1 population, and a cisplatin 1-h IC50 of approximately 100 μM. Treatment of MDA-231 cells in monolayer with cisplatin for 1 h, subsequently grown as spheroids, increased steady-state TGF-β1 mRNA levels, secretion of active TGF-β, cellular Cdk2 activity, pRb phosphorylation, and p21 protein levels, while downregulating p27. Accumulation of cells in G2M and progression into S were noted 48 h after treatment with 100 μM cisplatin. We tested whether drug-induced upregulation of TGF-β1 and p21, perhaps by preventing cell cycle progression, were protective mechanisms against drug-mediated toxicity by using neutralizing anti-TGF-β antibodies. Anti-TGF-β antibodies diminished the induction of p21, enhanced the activation of Cdk2, and facilitated progression into S and G2M following cisplatin treatment. This resulted in a >twofold enhancement of drug-induced DNA fragmentation and a shift in the cisplatin 1-h IC50 from 100 to <10 μM. These data suggest that tumor cell TGF-β1 may protect from DNA damage and that postchemotherapy administration of TGF-β inhibitors may facilitate progression beyond G1/S, potentially increasing the efficacy of cytotoxic chemotherapy.

Original languageEnglish (US)
Pages (from-to)350-359
Number of pages10
JournalExperimental Cell Research
Volume245
Issue number2
DOIs
StatePublished - Dec 15 1998

Keywords

  • Apoptosis
  • Breast carcinoma
  • Cell cycle
  • Cisplatin
  • Spheroids
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'Blockade of tumor cell transforming growth factor-βs enhances cell cycle progression and sensitizes human breast carcinoma cells to cytotoxic chemotherapy'. Together they form a unique fingerprint.

  • Cite this