Chung Wen-Cheng, Wang Wei, Challagundla Lavanya, Moore Charles D, Egan Sean E, Xu Keli
Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS, USA.
Cancer Center and Research Institute, University of Mississippi Medical Center, Jackson, MS, USA.
Oncogenesis. 2025 Jan 31;14(1):2. doi: 10.1038/s41389-025-00545-6.
Notch signaling is altered in breast cancer. Recent studies highlighted both tumor-suppressive and oncogenic roles for Notch in this tissue. The function of Jagged1, the most highly expressed Notch ligand in the mammary gland, is not well defined. Here we report that deletion of Jagged1 in the mammary epithelium of virgin mice led to expansion of the mammary stem cell (MaSC) compartment and defective luminal differentiation associated with decreased expression of the progesterone receptor (PR). In contrast, deletion of Jagged1 in alveolar cells of pregnant mice had no effect on alveolar and lactogenic differentiation or post-lactational involution. Interestingly, deletion of Jagged1 promoted mouse mammary tumor formation from luminal cells but suppressed them from basal cells, associated with downregulation of Notch target genes Hey1 and Hey2, respectively. In agreement with mouse experiments, high expression of JAG1 and HEY1 are associated with better overall survival among patients with luminal tumors, whereas high expression of JAG1 and HEY2 are both associated with worse overall survival in basal subtype of human breast cancer. These results identified Jagged1 as an important regulator of mammary epithelial hierarchy and revealed differential roles of Jagged1-mediated Notch signaling in different subtypes of breast cancer arising from distinct cell types.
Notch信号通路在乳腺癌中发生改变。最近的研究强调了Notch在该组织中的肿瘤抑制和致癌作用。Jagged1是乳腺中表达最高的Notch配体，其功能尚未明确界定。在此我们报告，在未孕小鼠的乳腺上皮中缺失Jagged1会导致乳腺干细胞（MaSC）区室扩张以及与孕激素受体（PR）表达降低相关的管腔分化缺陷。相比之下，在怀孕小鼠的肺泡细胞中缺失Jagged1对肺泡和泌乳分化或泌乳后退化没有影响。有趣的是，缺失Jagged1促进了管腔细胞来源的小鼠乳腺肿瘤形成，但抑制了基底细胞来源的肿瘤形成，分别与Notch靶基因Hey1和Hey2的下调相关。与小鼠实验一致，JAG1和HEY1的高表达与管腔型肿瘤患者更好的总生存率相关，而JAG1和HEY2的高表达均与人类基底型乳腺癌患者更差的总生存率相关。这些结果确定Jagged1是乳腺上皮层级的重要调节因子，并揭示了Jagged1介导的Notch信号通路在源自不同细胞类型的不同亚型乳腺癌中的不同作用。
