乳腺癌的发生与乳腺发育过程的调节改变有关。因此，更好地了解正常乳腺发育可以揭示正常细胞如何重新编程变成恶性的可能机制。 E2F 1-4 是 E2F 转录因子家族的一部分，在乳腺发育中发挥着不同的作用，但人们对 E2F5 的作用知之甚少。 scRNAseq 和预测特征工具的结合证明了乳腺中存在 E2F5，并显示了乳腺发育的各个阶段中预测活性的变化。为了测试 E2F5 调节乳腺功能的假设，我们生成了乳腺特异性 E2F5 敲除小鼠模型，导致乳腺发育发生适度变化。然而，经过长时间的潜伏期后，E2F5条件性敲除小鼠出现了高度转移性乳腺肿瘤。全基因组测序揭示了显着的肿瘤间异质性。 RNAseq 和蛋白质分析发现 Cyclin D1 水平发生改变，与 MMTV-Neu 肿瘤相似，表明 E2F5 条件敲除乳腺和肿瘤可能依赖于 Cyclin D1。肿瘤移植显示淋巴结转移，这些转移通过在免疫能力强的受体中进行连续移植而富集。基于这些发现，我们提出 E2F5 的缺失会导致 Cyclin D1 的调节发生改变，从而促进长潜伏期后转移性乳腺肿瘤的发展。更重要的是，这项研究表明，乳腺中 E2F5 的条件性缺失会导致肿瘤形成，揭示了其作为转录因子调节通常会产生肿瘤抑制功能的基因网络的作用。© 2024。作者。

Development of breast cancer is linked to altered regulation of mammary gland developmental processes. A better understanding of normal mammary gland development can thus reveal possible mechanisms of how normal cells are re-programmed to become malignant. E2Fs 1-4 are part of the E2F transcription factor family with varied roles in mammary development, but little is known about the role of E2F5. A combination of scRNAseq and predictive signature tools demonstrated the presence of E2F5 in the mammary gland and showed changes in predicted activity during the various phases of mammary gland development. Testing the hypothesis that E2F5 regulates mammary function, we generated a mammary-specific E2F5 knockout mouse model, resulting in modest mammary gland development changes. However, after a prolonged latency the E2F5 conditional knockout mice developed highly metastatic mammary tumors. Whole genome sequencing revealed significant intertumor heterogeneity. RNAseq and protein analysis identified altered levels of Cyclin D1, with similarities to MMTV-Neu tumors, suggesting that E2F5 conditional knockout mammary glands and tumors may be dependent on Cyclin D1. Transplantation of the tumors revealed metastases to lymph nodes that were enriched through serial transplantation in immune competent recipients. Based on these findings, we propose that loss of E2F5 leads to altered regulation of Cyclin D1, which facilitates the development of metastatic mammary tumors after long latency. More importantly, this study demonstrates that conditional loss of E2F5 in the mammary gland leads to tumor formation, revealing its role as a transcription factor regulating a network of genes that normally result in a tumor suppressor function.© 2024. The Author(s).