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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.; De Benedictis, Ilaria; Gómez-Aleza, Clara; Da Silva-Álvarez, Sabela; Troulé, Kevin; Gómez-López, Gonzalo; Alcazar, Noelia; Palmero, Ignacio; Collado, Manuel; Serrano, Manuel; Gonzalez-Suarez, Eva
Developmental cell, 06/2021, Volume: 56, Issue: 12Journal Article
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. Display omitted •Rank expression delays mammary tumor onset in oncogene-driven models•Activation of Rank signaling induces senescence through p16/p19•Rank-induced senescence in luminal cells increases basal and luminal stemness•Rank-induced senescent cells promote mammary tumor growth Rank pathway inhibitors have emerged as therapeutic options for breast cancer prevention and treatment. Benitez et al. show that activation of Rank signaling induces senescence, which paradoxically delays tumor onset and incidence but promotes tumor aggressiveness. Treatment with senolytics eliminates Rank-induced senescent cells, reducing stemness and breast cancer growth.
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