AIM: To examine whether trans-10, cis-12 CLA (t10c12)or cis-9, trans-11 CLA (c9 t11) inhibits heregulin (H RG)-β-stimulated cell growth and HRG-β-ErbB3 signaling in HT-29 cells.METHODS: We cultured HT-29 cells in the absence or presence of the CLA isomers and/or the ErbB3 ligand HRG-β. MTT assay, [3H]thymidine incorporation, Annexin V staining, RT-PCR, West blotting, immunoprecipitation,and in vitro kinase assay were performed.RESULTS: HRG-β increased cell growth, but did not prevent t10c12-induced growth inhibition. T10c12 inhibited DNA synthesis and induced apoptosis of HT-29 cells, whereas c9t11 had no effect. T10c12 decreased the levels of ErbB1,ErbB2, and ErbB3 proteins and transcripts in a dose-dependent manner, whereas cgt11 had no effect. Immunoprecipitation/West blot studies revealed that t10c12 inhibited HRG-β-stimulated phosphorylation of ErbB3, recruitment of the p85 subunit of phosphoinositide 3-kinase (PI3K) to ErbB3, ErbB3-associated PI3K activities, and phosphorylation ofAkt. However, c9t11 had no effect on phospho Akt levels.Neither t10c12 nor c9t11 had any effect on HRG-β-induced phosphorylation of ERK-1/2.CONCLUSION: These results indicate that the inhibition of HT-29 cell growth by t10c12 may be induced via its modulation of ErbB3 signaling leading to inhibition of Akt activation.