Role of AIB1 in YAP/TAZ-TEAD signaling in progression of early stage breast cancer

项目摘要/摘要 核共激活子AIB1是NCOA/SRC/p160家族的成员，已知可被扩增和 过度表达的乳腺癌。AIB1作为支架蛋白促进转录因子的组装， 从而促进ER、NFκB、AP-1等致癌因子的转录活性。我们有 先前显示AIB1共激活被ANCO1肿瘤抑制因子直接抑制，ANCO1肿瘤抑制因子丢失 在乳腺癌的发展过程中。因此，AIB1促进增殖和疾病进展。此外，在 乳腺癌小鼠模型，组织特异性AIB1基因敲除可降低发病率和延迟 肿瘤发生学。AIB1含有一个N-末端的bHLH/PAS激活域，据报道它与TEAD相互作用， 河马途径的效应者。尽管AIB1和TEAD之间的相互作用已经被证明是 由AIB1的bHLH/PAS结构域介导，蛋白质-蛋白质相互作用的生理效应是 不清楚。由于这两种蛋白都是潜在的致癌蛋白，它们在正常组织中的相互作用机制及其程度 在恶性组织中的相互作用，可能具有极端的后果，并解释了AIB1的致癌作用。 与其他Teads反式激活剂相比，人们对其导致的特定靶基因表达知之甚少 来自AIB1-TEAD交互。我们假设AIB1在反式激活结构域附近与TEAD结合， 与其他共激活因子和抑制因子合作，有选择地招募TEAD作为靶基因的启动子。 我们的目标是定义AIB1和TEAD之间的相互作用机制(目标1A-C)，了解 与乳腺癌进展相关的结合(AIM 1D)，并描述了AIB1-tead共同占据的基因座 基因组(目标2)。成功完成这些目标将阐明AIB1-TEAD的后果 乳腺癌进展过程中的相互作用，以及ANCO1抑制的丧失。

Project Summary/Abstract The nuclear co-activator AIB1 is a member of the NCOA/SRC/p160 family and is known to be amplified and overexpressed breast cancer. AIB1 acts as a scaffolding protein to facilitate assembly of transcription factors, and thereby promotes the transcriptional activity of oncogenic factor such as ER, NFκB, and AP-1. We have previously shown AIB1 co-activation to be directly suppressed by the ANCO1 tumor suppressor, which is lost during breast cancer progression. As a result, AIB1 promotes proliferation and disease progression. Further, in breast cancer mouse models, tissue specific AIB1 knockout reduces disease incidence and delays tumorigenesis. AIB1 contains a N-terminal bHLH/PAS activation domain that reportedly interacts with TEAD, effector of the Hippo pathway. Though the interaction between the AIB1 and TEAD has been shown to be mediated by the bHLH/PAS domain of AIB1, the physiological effects of the protein-protein interaction are unclear. As both proteins are potently oncogenic, their mechanism of interaction in normal tissue, and the extent of the interaction in malignant tissue, may be of extreme consequence and explain the oncogenic role of AIB1. Compared to other transactivators of TEADs, little is known about the specific target gene expression that results from AIB1-TEAD interaction. We hypothesize that the AIB1 binds TEAD near the transactivation domain, cooperates with other co-activators and repressors, and recruits TEAD selectively to promoters of target genes. We aim to define a mechanism of interaction between AIB1 and TEAD (Aim 1A-C), understand perturbations in binding associated with breast cancer progression (Aim 1D), and profile the loci of AIB1-TEAD co-occupancy on the genome (Aim 2). Successful completion of these aims will elucidate the consequences of AIB1-TEAD interaction during breast cancer progression, as well as the loss of ANCO1 suppression.