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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)
Publ. Version/Full Text DOI PMC
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords 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
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 1534-5807
e-ISSN 1878-1551
Journal Developmental Cell
Quellenangaben Volume: 56, Issue: 12, Pages: 1727-1741.e7 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Experimental Genetics (IEG)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500692-001
Grants 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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