CAF, A COACTIVATOR OF FOS, AND BREAST CANCER

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Recent studies in our laboratory have established that progression to invasive human breast cancer is accompanied by the activation of tissue factor (TF)-expressing myofibroblasts, a stromal response to carcinoma cell-derived members of the TGF-beta family of growth factors. Futhermore, TGF-beta1-dependent activation of TF gene transcription in myofibroblast-like cells in vitro requires c-Fos-containing AP-1 DNA- binding heterodimers and TF basal promoter-specific factor with functional properties characteristic of a transcriptional coactivator. This putative coactivator of Fos (CAF) appears distinct from CBP/p300 family of coactivators, but like CBP/p300, functionally interacts with both c-Fos and the adenovirus E1A12s protein. Importantly, the ability of CAF to mediate functional interactions with c-Fos is dependent upon TGF-beta1 signaling. In this research, we will 1) map E1A domains which specifically interact with CAF, 2) utilize this information to partially characterize CAF and to isolate CAF protein and cDNA for sequence analysis, 3) determine how the functional activity of CAF is modulated by TGF-beta1 signaling, and 4) probe for the expression of CAF in breast cancer myofibroblasts in vivo. These studies should illuminate a novel downstream target of TGF-beta signaling in myofibroblasts and may ultimately establish CAF as an essential mediator of carcinoma cell- stromal interactions which contribute to breast cancer progression.