Aberrant Notch signaling is implicated in several cancers, including breast cancer. However, the mechanistic details of the specific receptors and function of ligand-mediated Notch signaling that promote breast cancer remains elusive. In our studies we show that DLL1, a Notch signaling ligand, is significantly overexpressed in ERα+ luminal breast cancer. Intriguingly, DLL1 overexpression correlates with poor prognosis in ERα+ luminal breast cancer, but not in other subtypes of breast cancer. In addition, this effect is specific to DLL1, as other Notch ligands (DLL3, JAGGED1, and JAGGED2) do not influence the clinical outcome of ERα+ patients. Genetic studies show that DLL1-mediated Notch signaling in breast cancer is important for tumor cell proliferation, angiogenesis, and cancer stem cell function. Consistent with prognostic clinical data, we found the tumor-promoting function of DLL1 is exclusive to ERα+ luminal breast cancer, as loss of DLL1 inhibits both tumor growth and lung metastasis of luminal breast cancer. Importantly, we find that estrogen signaling stabilizes DLL1 protein by preventing its proteasomal and lysososmal degradations. Moreover, estrogen inhibits ubiquitination of DLL1. Together, our results highlight an unexpected and novel subtype-specific function of DLL1 in promoting luminal breast cancer that is regulated by estrogen signaling. Our studies also emphasize the critical role of assessing subtype-specific mechanisms driving tumor growth and metastasis to generate effective subtype-specific therapeutics.

中文翻译：

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依赖雌激素的DLL1介导的Notch信号促进管腔型乳腺癌。

Notch信号异常参与多种癌症，包括乳腺癌。然而，促进乳腺癌的特异性受体的机制细节和配体介导的Notch信号传导的功能仍然难以捉摸。在我们的研究中，我们显示了Notch信号配体DLL1在ERα+腔内乳腺癌中显着过表达。有趣的是，DLL1过表达与ERα+管腔型乳腺癌的不良预后相关，而与其他亚型乳腺癌无关。此外，该效应对DLL1特有，因为其他Notch配体（DLL3，JAGGED1和JAGGED2）不会影响ERα+患者的临床结局。遗传研究表明，DLL1介导的Notch信号在乳腺癌中对于肿瘤细胞增殖，血管生成和癌症干细胞功能很重要。与预后的临床数据一致，我们发现DLL1的促肿瘤功能是ERα+腔内乳腺癌所独有的，因为DLL1的丢失同时抑制了腔内乳腺癌的肿瘤生长和肺转移。重要的是，我们发现雌激素信号传导可通过阻止其蛋白酶体和溶酶体降解来稳定DLL1蛋白。此外，雌激素抑制DLL1的泛素化。在一起，我们的结果突出了DLL1在促进由雌激素信号调节的管腔型乳腺癌中出乎意料且新颖的亚型特异性功能。我们的研究还强调评估驱动肿瘤生长和转移以产生有效的亚型特异性疗法的亚型特异性机制的关键作用。因为DLL1的丢失同时抑制了管腔型乳腺癌的肿瘤生长和肺转移。重要的是，我们发现雌激素信号传导可通过阻止其蛋白酶体和溶酶体降解来稳定DLL1蛋白。此外，雌激素抑制DLL1的泛素化。在一起，我们的结果突出了DLL1在促进由雌激素信号调节的管腔型乳腺癌中出乎意料且新颖的亚型特异性功能。我们的研究还强调评估驱动肿瘤生长和转移以产生有效的亚型特异性疗法的亚型特异性机制的关键作用。因为DLL1的丢失同时抑制了管腔乳腺癌的肿瘤生长和肺转移。重要的是，我们发现雌激素信号传导可通过阻止其蛋白酶体和溶酶体降解来稳定DLL1蛋白。此外，雌激素抑制DLL1的泛素化。在一起，我们的结果突出了DLL1在促进由雌激素信号调节的管腔型乳腺癌中出乎意料且新颖的亚型特异性功能。我们的研究还强调评估驱动肿瘤生长和转移以产生有效的亚型特异性疗法的亚型特异性机制的关键作用。我们的研究结果突显了DLL1在促进由雌激素信号调节的管腔型乳腺癌中出乎意料且新颖的亚型特异性功能。我们的研究还强调评估驱动肿瘤生长和转移以产生有效的亚型特异性疗法的亚型特异性机制的关键作用。我们的研究结果突显了DLL1在促进由雌激素信号调节的管腔型乳腺癌中出乎意料且新颖的亚型特异性功能。我们的研究还强调评估驱动肿瘤生长和转移以产生有效的亚型特异性疗法的亚型特异性机制的关键作用。