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During the progression of human cancers, normal cells acquire genetic and epigenetic changes in the signaling pathways that govern their proliferation, resulting in uncontrolled growth and tumor formation. Oncogenic Ras and Transforming Growth Factor-Beta are known to cooperate in promoting malignant transformation, yet the mechanism by which they interact has not been established. Here, we present novel mechanisms through which Transforming Growth Factor-Beta interacts with two Ras-related proteins, R-Ras and TC21, to transform mammary epithelial cells.