Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain.
Oncobell, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain; Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Dev Cell. 2021 Jun 21;56(12):1727-1741.e7. doi: 10.1016/j.devcel.2021.04.022. Epub 2021 May 17.
Rank signaling enhances stemness in mouse and human mammary epithelial cells (MECs) and mediates mammary tumor initiation. Mammary tumors initiated by oncogenes or carcinogen exposure display high levels of Rank and Rank pathway inhibitors have emerged as a new strategy for breast cancer prevention and treatment. Here, we show that ectopic Rank expression in the mammary epithelia unexpectedly delays tumor onset and reduces tumor incidence in the oncogene-driven Neu and PyMT models. Mechanistically, we have found that ectopic expression of Rank or exposure to Rankl induces senescence, even in the absence of other oncogenic mutations. Rank leads to DNA damage and senescence through p16/p19. Moreover, RANK-induced senescence is essential for Rank-driven stemness, and although initially translates into delayed tumor growth, eventually promotes tumor progression and metastasis. We uncover a dual role for Rank in the mammary epithelia: Rank induces senescence and stemness, delaying tumor initiation but increasing tumor aggressiveness.
信号转导增强了小鼠和人乳腺上皮细胞（MECs）的干性，并介导了乳腺肿瘤的起始。由致癌基因或致癌物暴露引发的乳腺肿瘤表现出高水平的 Rank 和 Rank 途径抑制剂，已成为乳腺癌预防和治疗的新策略。在这里，我们表明，乳腺上皮细胞中异位 Rank 的表达出人意料地延迟了肿瘤的发生，并降低了致癌基因驱动的 Neu 和 PyMT 模型中的肿瘤发生率。从机制上讲，我们发现异位表达 Rank 或暴露于 Rankl 会诱导衰老，即使没有其他致癌突变也是如此。Rank 通过 p16/p19 导致 DNA 损伤和衰老。此外，RANK 诱导的衰老对于 Rank 驱动的干性是必不可少的，尽管最初会导致肿瘤生长延迟，但最终会促进肿瘤的进展和转移。我们揭示了 Rank 在乳腺上皮细胞中的双重作用：Rank 诱导衰老和干性，延迟肿瘤起始，但增加肿瘤侵袭性。
