Abstract
MAP17 is a small, 17-kDa, non-glycosylated membrane protein that is overexpressed in a percentage of carcinomas. In the present work, we have analyzed the role of MAP17 expression during mammary cancer progression. We have found that MAP17 is expressed in 60% human mammary tumors while it is not expressed in normal or benign neoplasias. MAP17 levels increased with breast tumor stage and were strongly correlated with mammary tumoral progression. A significant increase in the levels of reactive oxygen species (ROS) was observed in MAP17-expressing cells, as compared with parental cells. This increase was further paralleled by an increase in the tumorigenic capacity of carcinoma cells but not in immortal non-tumoral breast epithelial cells, which provides a selective advantage once tumorigenesis has begun. Expression of specific MAP17 shRNA in protein-expressing tumor cells reduced their tumorigenic capabilities, which suggests that this effect is dependent upon MAP17 protein expression. Our data show that ROS functions as a second messenger that enhances tumoral properties, which are inhibited in non-tumoral cells. We have found that p38α activation mediates this response. MAP17 triggers a ROS-dependent, senescence-like response that is abolished in the absence of p38a activation. Furthermore, in human breast tumors, MAP17 activation is correlated with a lack of phosphorylation of p38α. Therefore, MAP17 is overexpressed in late-stage breast tumors, in which oncogenic activity relies on p38 insensitivity to induce intracellular ROS.
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Acknowledgements
We thank Augusto Silva and Ricardo Sanchez Prieto for their critical reading of the manuscript and valuable suggestions. This work was supported by grants from the Spanish Ministry of Science and Innovation and FEDER (SAF2009-08605), Consejeria de Ciencia e Innovacion and Consejeria de Salud of the Junta de Andalucia (CTS-6844 and PI-0142). AC's laboratory is also funded by a fellowship from the Fundacion Oncologica FERO, supported by Fundació Josep Botet.
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Guijarro, M., Vergel, M., Marin, J. et al. p38α limits the contribution of MAP17 to cancer progression in breast tumors. Oncogene 31, 4447–4459 (2012). https://doi.org/10.1038/onc.2011.619
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DOI: https://doi.org/10.1038/onc.2011.619
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