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Benitez, S.* ; Cordero, A.* ; Santamaria, P.G.* ; Redondo-Pedraza, J.* ; Rocha, A.S.* ; Collado-Solé, A.* ; Jimenez, M.* ; Sanz-Moreno, A. ; Yoldi, G.* ; Santos, J.C.* ; De Benedictis, I.* ; Gómez-Aleza, C.* ; Da Silva-Álvarez, S.* ; Troulé, K.* ; Gómez-López, G.* ; Alcazar, N.* ; Palmero, I.* ; Collado, M.* ; Serrano, M.* ; Gonzalez-Suarez, E.*

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

Dev. Cell 56, 1727-1741.e7 (2021)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Breast Cancer ; Mammary Gland ; Metastasis ; Receptor Activator Of Nfkb ; Senescence ; Senolytics ; Stemness; Oncogene-induced Senescence; Differential Expression Analysis; Cellular Senescence; In-vivo; Secretory Phenotype; Transgenic Mice; Cells; Cancer; Proliferation; Induction
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 1534-5807
e-ISSN 1878-1551
Zeitschrift Developmental Cell
Quellenangaben Band: 56, Heft: 12, Seiten: 1727-1741.e7 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500692-001
Förderungen FPI
FPI Severo Ochoa Fellowship
Fundacio La Maratode TV3
European Research Council (ERC) under the European Union
FEDER funds/European Regional Development Fund (ERDF) (a way to build Europe)
Agencia Estatal de Investigacion (AEI)
DOI 10.1016/j.devcel.2021.04.022
WOS ID WOS:000664347400005
PubMed ID 34004159
Erfassungsdatum 2021-06-25
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