Research Papers:

This article has been corrected. Correction in: Oncotarget. 2017; 8:50323.

Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation

Sara Lázaro, Miriam Pérez-Crespo, Ana Belén Enguita, Pilar Hernández, Jesús Martínez-Palacio, Marta Oteo, Julien Sage, Jesús M. Paramio and Mirentxu Santos _

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Oncotarget. 2017; 8:4373-4386. https://doi.org/10.18632/oncotarget.13875

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Sara Lázaro1, Miriam Pérez-Crespo1, Ana Belén Enguita2, Pilar Hernández1, Jesús Martínez-Palacio1, Marta Oteo3, Julien Sage4,5, Jesús M. Paramio1,6,7, Mirentxu Santos1,6,7

1Molecular Oncology Unit Institute of Biomedical Investigation University Hospital “12 de Octubre”, Madrid, Spain

2Pathology Department Institute of Biomedical Investigation University Hospital “12 de Octubre”, Madrid, Spain

3Biomedical Applications and Pharmacokinetics CIEMAT (ed 70A), Madrid, Spain

4Department of Pediatrics, Stanford University, Stanford, USA

5Department of Genetics. Stanford University, CCSR Rm. 1215a. Stanford, California, USA

6Molecular Oncology, Institute of Biomedical Investigation University Hospital “12 de Octubre”, Madrid, Spain

7Centro de Investigaciones Biomédicas en Red de Cáncer (CIBERONC), Madrid, Spain

Correspondence to:

Jesús M. Paramio, email: [email protected]

Mirentxu Santos, email: [email protected]

Keywords: retinoblastoma family, lung cancer, urethane, DHPN

Received: January 13, 2016     Accepted: December 05, 2016     Published: December 10, 2016


Lung cancer is a deadly disease with increasing cases diagnosed worldwide and still a very poor prognosis. While mutations in the retinoblastoma (RB1) tumor suppressor have been reported in lung cancer, mainly in small cell lung carcinoma, the tumor suppressive role of its relatives p107 and p130 is still a matter of debate. To begin to investigate the role of these two Rb family proteins in lung tumorigenesis, we have generated a conditional triple knockout mouse model (TKO) in which the three Rb family members can be inactivated in adult mice. We found that ablation of all three family members in the lung of mice induces tumorlets, benign neuroendocrine tumors that are remarkably similar to their human counterparts. Upon chemical carcinogenesis, DHPN and urethane accelerate tumor development; the TKO model displays increased sensitivity to DHPN, and urethane increases malignancy of tumors. All the tumors developing in TKO mice (spontaneous and chemically induced) have neuroendocrine features but do not progress to fully malignant tumors. Thus, loss of Rb and its family members confers partial tumor susceptibility in neuroendocrine lineages in the lungs of mice. Our data also imply the requirement of other oncogenic signaling pathways to achieve full transformation in neuroendocrine lung lesions mutant for the Rb family.

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