Transcription factors critical for the transition of normal breast epithelium to ductal carcinoma in situ (DCIS) and invasive breast cancer are not clearly defined. Here, we report that the expression of a subset of YAP-activated and YAP-repressed genes in normal mammary and early-stage breast cancer cells is dependent on the nuclear co-activator AIB1. Gene expression, sequential ChIP, and ChIP-seq analyses show that AIB1 and YAP converge upon TEAD for transcriptional activation and repression. We find that AIB1-YAP repression of genes at the 1q21.3 locus is mediated by AIB1-dependent recruitment of ANCO1, a tumor suppressor whose expression is progressively lost during breast cancer progression. Reducing ANCO1 reverts AIB1-YAP-dependent repression, increases cell size, and enhances YAP-driven aberrant 3D growth. Loss of endogenous ANCO1 occurs during DCIS xenograft progression, a pattern associated with poor prognosis in human breast cancer. We conclude that increased expression of AIB1-YAP co-activated targets coupled with a loss of normal ANCO1 repression is critical to patterns of gene expression that mediate malignant progression of early-stage breast cancer.

中文翻译：

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AIB1/YAP 靶点上 ANCO1 抑制的丧失推动了乳腺癌的进展。

对于正常乳腺上皮细胞向导管原位癌 (DCIS) 和浸润性乳腺癌转变的关键转录因子尚未明确定义。在这里，我们报告在正常乳腺和早期乳腺癌细胞中 YAP 激活和 YAP 抑制基因子集的表达依赖于核共激活因子 AIB1。基因表达、连续 ChIP 和 ChIP-seq 分析表明，AIB1 和 YAP 会聚在 TEAD 上以进行转录激活和抑制。我们发现 AIB1-YAP 对 1q21.3 基因座基因的抑制是由 AIB1 依赖性募集 ANCO1 介导的，ANCO1 是一种肿瘤抑制因子，其表达在乳腺癌进展过程中逐渐丧失。减少 ANCO1 可恢复 AIB1-YAP 依赖性抑制，增加细胞大小，并增强 YAP 驱动的异常 3D 生长。内源性 ANCO1 的缺失发生在 DCIS 异种移植进展过程中，这种模式与人类乳腺癌的不良预后相关。我们得出结论，AIB1-YAP 共激活靶标的表达增加以及正常 ANCO1 抑制的丧失对于介导早期乳腺癌恶性进展的基因表达模式至关重要。