RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness

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...

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Detalles Bibliográficos
Autores: Benítez, Sandra, Cordero, Alex, Santamaría, Patricia G., Redondo Pedraza, Jaime, Rocha, Ana S., Collado-Solé, Alejandro, Jimenez, Maria, Sanz Moreno, Adrian, Yoldi, Guillermo, Santos, Juliana C., Benedictis, Ilaria De, Gómez Aleza, Clara, Silva Álvarez, Sabela Da, Troulé, Kevin, Gómez López, Gonzalo, Alcazar, Noelia, Palmero, Ignacio, Collado, Manuel, Serrano Marugán, Manuel, González Suárez, Eva
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/177852
Acceso en línea:https://hdl.handle.net/2445/177852
Access Level:acceso abierto
Palabra clave:Càncer de mama
Metàstasi
Cicle cel·lular
Breast cancer
Metastasis
Cell cycle
Descripción
Sumario: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.

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