三阴性乳腺癌（TNBC）的特点是缺乏雌激素（ER）受体、孕激素受体（PR）和人表皮生长因子受体2（HER2），标准的受体靶向治疗无效。 FOXC1 是一种在许多癌症中异常过度表达的转录因子，可促进 TNBC 的生长、转移和干细胞样特性。然而，FOXC1 的分子功能尚不清楚，部分原因是 TNBC 的异质性。在这里，我们表明，尽管 FOXC1 调节 TNBC 中的许多癌症标志，但其功能在不同细胞系中是不同的，尤其是 FOXC1 丢失时对 CDK4/6 抑制剂的不同反应。尽管存在这种功能异质性，但我们表明 FOXC1 调节关键癌基因和肿瘤抑制因子，并确定了一组在 TNBC 细胞系中保守的核心 FOXC1 峰。我们将 ER 相关且药物靶向的核受体 NR2F2 确定为 FOXC1 的辅助因子。最后，我们证明 TNBC 中的核心 FOXC1 靶标受到 ER 乳腺癌中先锋因子 FOXA1 和核受体 NR2F2 的并行调节。© 2024 作者。

Triple-negative breast cancer (TNBC) is characterized by lack of the estrogen (ER) receptor, progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2), and standard receptor-targeted therapies are ineffective. FOXC1, a transcription factor aberrantly overexpressed in many cancers, drives growth, metastasis, and stem-cell-like properties in TNBC. However, the molecular function of FOXC1 is unknown, partly due to heterogeneity of TNBC. Here, we show that although FOXC1 regulates many cancer hallmarks in TNBC, its function is varied in different cell lines, highlighted by the differential response to CDK4/6 inhibitors upon FOXC1 loss. Despite this functional heterogeneity, we show that FOXC1 regulates key oncogenes and tumor suppressors and identify a set of core FOXC1 peaks conserved across TNBC cell lines. We identify the ER-associated and drug-targetable nuclear receptor NR2F2 as a cofactor of FOXC1. Finally, we show that core FOXC1 targets in TNBC are regulated in parallel by the pioneer factor FOXA1 and the nuclear receptor NR2F2 in ER + breast cancer.© 2024 The Author(s).