CAF, A COACTIVATOR OF FOS, AND BREAST CANCER

我们实验室最近的研究已经证实， 侵袭性人类乳腺癌伴随着组织的活化， 表达TF因子的肌成纤维细胞，一种对癌的间质反应 TGF-β生长因子家族的细胞衍生成员。 Fuxyline，TGF-β 1依赖性激活TF基因转录， 体外肌成纤维细胞样细胞需要含c-Fos的AP-1 DNA， 结合异源二聚体和TF基础启动子特异性因子， 转录辅激活因子的功能特性。 这种推定的Fos共激活因子（CAF）似乎与CBP/p300不同 与CBP/p300一样，共激活因子家族在功能上与 c-Fos和腺病毒E1 A12 s蛋白。 重要的是， CAF介导与c-Fos的功能性相互作用依赖于 TGF-β 1信号传导。 在这项研究中，我们将1）映射E1 A域， 特别是与CAF互动，2）利用这些信息部分地 鉴定CAF并分离CAF蛋白和cDNA用于测序 分析，3）确定CAF的功能活性如何被调节 通过TGF-β 1信号传导，和4）探测乳腺中CAF的表达 体内的癌肌成纤维细胞。 这些研究应该能启发一部小说 在肌成纤维细胞中TGF-β信号传导的下游靶点， 最终确立CAF作为癌细胞的重要介质， 间质相互作用有助于乳腺癌的进展。

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.