Transforming growth factor (TGF)-beta in conjunction with H-ras activation promotes malignant progression of MCF10A breast epithelial cells.

To address how transforming growth factor (TGF)-beta and oncogenic H-ras signal transduction pathways interact with each other in the malignant progression of breast epithelial cells, we investigated the role of TGF-beta signaling pathway in invasive and migrative properties of H-ras-transformed MCF10A human breast epithelial cells in this study. Here we show that TGF-beta treatment significantly enhanced invasion and migration of H-ras MCF10A cells. H-ras-mediated activation of p38 MAPK and ERK-1/2 was stimulated by TGF-beta. TGF-beta increased expression of matrix metalloproteinase (MMP)-2 through transcriptional activation while TGF-beta-stimulated MMP-9 up-regulation did not occur at transcription level. Activation of p38 MAPK pathway was required for TGF-beta-induced cell migration, invasion and MMP-2/-9 up-regulation, indicating a critical role of p38 MAPK signaling in TGF-beta-promoted tumor progression of H-ras-activated cells. ERKs signaling was also crucial for TGF-beta-enhanced invasive and migrative phenotypes but the up-regulation of MMP-2/-9 was not dependent on ERKs activity. Taken together, we show that TGF-beta promotes H-ras-mediated cell migration and invasive phenotypes in which p38 MAPK and ERKs signaling pathways are involved. Our findings revealing how H-ras and TGF-beta signal pathways interact with each other in MCF10A human breast cells may provide an insight into molecular mechanisms for contribution of TGF-beta to a malignant progression of breast cancer in collaboration with activated H-ras.