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Título: | RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness |
Autor: | Benítez, Sandra; Cordero, Alex; Santamaría, Patricia G. CSIC ORCID; Redondo-Pedraza, Jaime; Rocha, Ana S.; Collado-Solé, Alejandro; Jiménez, María ; Sanz-Moreno, Adrián; Yoldi, Guillermo; Santos, Juliana C.; Benedictis, Ilaria De; Gómez-Aleza, Clara; Silva-Alvarez, S. da; Troulé, Kevin; Gómez-López, Gonzalo; Alcázar, Noelia; Palmero, Ignacio CSIC ORCID; Collado, Manuel; Serrano, Manuel; González-Suarez, Eva | Palabras clave: | Breast cancer Mammary gland Receptor activator of NFkB Senescence Senolytics Stemness Metastasis |
Fecha de publicación: | 21-jun-2021 | Editor: | Elsevier | Citación: | Developmental Cell 56(12): 1727-1741.e7 (2021) | Resumen: | 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. | Descripción: | © 2021 The Authors. | Versión del editor: | http://dx.doi.org/10.1016/j.devcel.2021.04.022 | URI: | http://hdl.handle.net/10261/265429 | DOI: | 10.1016/j.devcel.2021.04.022 | ISSN: | 1534-5807 | E-ISSN: | 1878-1551 |
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RANK_Links_Senescence_Benítez_PV_Art2021.pdf | 5,5 MB | Adobe PDF | Visualizar/Abrir |
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