Aberrant activation of the cAMP/CREB and TGFß/Smad signaling is involved in breast cancer progression. I investigated the interplay of these pathways in breast cancer cells in 2-dimensional (2D) and 3D cultures. Simultaneous activation of both pathways affected gene expression differently as expected from the single responses. In 2D cultures, cAMP elevation increased TGFß responsiveness of some genes and TGFß-dependent Smad3 phosphorylation. Furthermore, cAMP elevation induced TGFß receptor I (TßRI) upregulation. The mechanism of this upregulation was further investigated by the use of inhibitors of transcription and histone modification, siRNAs and reporter constructs. Ectopic expression of TßRI mimicked the response to cAMP elevation. 3D-cultured cells showed different responses which were further investigated. Furthermore, morphological and functional changes were induced by cAMP elevation and TGFß. Taken together, this study suggests that, cAMP can interfere with TGFß signaling by upregulating TßRI and that cAMP and TGFß induce morphological and functional alterations independently of this mechanism.