SAP30 是转录共抑制子SIN3复合物的核心亚基，但其在基因调控和人类癌症中的作用知之甚少。在这里，我们发现SAP30是一种非突变的致癌蛋白，在50%以上的人类乳腺肿瘤中上调表达，并与乳腺癌患者不利的预后相关。在各种乳腺癌小鼠模型中，我们发现SAP30通过与SIN3A/3B的相互作用，促进肿瘤生长和转移。令人惊讶的是，SAP30的传统基因沉默作用对其促瘤作用并不是必需的。SAP30增强了乳腺癌细胞启动子的染色质可及性和RNA聚合酶II的占位，作为细胞运动、血管生成和淋巴管生成相关基因的共激活子，推动肿瘤进展。值得注意的是，SAP30与1个亚基形成同型二聚体，其中一个亚基通过其转活化结构域内特定的Phe186/200残基与SIN3A结合，另一个亚基通过招募MLL1参与转录共激活和乳腺肿瘤进展。总之，我们的发现揭示了SAP30在乳腺癌中代表了一种转录依赖性。

SAP30 is a core subunit of the transcriptional corepressor SIN3 complex, but little is known about its role in gene regulation and human cancer. Here, we show that SAP30 was a nonmutational oncoprotein upregulated in more than 50% of human breast tumors and correlated with unfavorable outcomes in patients with breast cancer. In various breast cancer mouse models, we found that SAP30 promoted tumor growth and metastasis through its interaction with SIN3A/3B. Surprisingly, the canonical gene silencing role was not essential for SAP30's tumor-promoting actions. SAP30 enhanced chromatin accessibility and RNA polymerase II occupancy at promoters in breast cancer cells, acting as a coactivator for genes involved in cell motility, angiogenesis, and lymphangiogenesis, thereby driving tumor progression. Notably, SAP30 formed a homodimer with 1 subunit binding to SIN3A and another subunit recruiting MLL1 through specific Phe186/200 residues within its transactivation domain. MLL1 was required for SAP30-mediated transcriptional coactivation and breast tumor progression. Collectively, our findings reveal that SAP30 represents a transcriptional dependency in breast cancer.