Transforming growth factor-I? (TGFI?) plays an important role in breast cancer metastasis. Here phosphoinositide 3-kinase (PI3K) signalling was found to play an essential role in the enhanced migration capability of fibroblastoid cells (FibRas) derived from normal mammary epithelial cells (EpH4) by transduction of oncogenic Ras (EpRas) and TGFI?1. While expression of the PI3K isoform p110I? was down-regulated in FibRas cells, there was an increase in the expression of p110I? and p110I? in the fibroblastoid cells. The PI3K isoform p110I? was found to specifically contribute to cell migration in FibRas cells, while p110I? contributed to the response in EpH4, EpRas and FibRas cells. Akt, a downstream targets of PI3K signalling, had an inhibitory role in the migration of transformed breast cancer cells, while Rac, Cdc42 and the ribosomal protein S6 kinase (S6K) were necessary for the response. Together our data reveal a novel specific function of the PI3K isoform p110I? in the migration of cells transformed by oncogenic H-Ras and TGF-I?1. A? 2010 Elsevier Inc.