CAF, A COACTIVATOR OF FOS, AND BREAST CANCER

我们实验室最近的研究已经证实了这一进展 人类浸润性乳腺癌伴随着组织的活化 因子(TF)表达的肌成纤维细胞--对癌症的间质反应 转化生长因子-β家族的细胞衍生成员。 此外，转化生长因子-β1依赖的血管生成因子基因转录的激活 体外培养的肌成纤维细胞样细胞需要含有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 转录辅助激活因子所特有的功能特性。 这个假定的Fos共激活子(Caf)似乎与CBP/p300不同 辅激活子家族，但像CBP/p300一样，在功能上与 C-Fos和腺病毒E1A12s蛋白。重要的是，这种能力 CAF介导与c-Fos的功能相互作用依赖于 转化生长因子-β1信号转导。在本研究中，我们将1)映射E1a结构域 具体地与CAF交互，2)利用该信息部分地 CAF的鉴定及CAF蛋白和cDNA的分离与测序 分析，3)确定CAF的功能活性是如何被调节的 通过转化生长因子-β1信号转导，以及4)CAF在乳腺中的表达 体内的癌性肌成纤维细胞。这些研究应该会对一部小说有所启发 肌成纤维细胞中转化生长因子-β信号的下游靶点 最终将CAF确立为癌细胞的重要介质- 导致乳腺癌进展的间质相互作用。

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.