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  • Original Article
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A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development

Oncogene volume 34, pages 4777–4790 (2015)Cite this article

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An Erratum to this article was published on 03 September 2015

This article has been updated

Abstract

Breast cancer is a major cause of mortality in women. The transcription factor SNAI2 has been implicated in the pathogenesis of several types of cancer, including breast cancer of basal origin. Here we show that SNAI2 is also important in the development of breast cancer of luminal origin in MMTV-ErbB2 mice. SNAI2 deficiency leads to longer latency and fewer luminal tumors, both of these being characteristics of pretumoral origin. These effects were associated with reduced proliferation and a decreased ability to generate mammospheres in normal mammary glands. However, the capacity to metastasize was not modified. Under conditions of increased ERBB2 oncogenic activity after pregnancy plus SNAI2 deficiency, both pretumoral defects—latency and tumor load—were compensated. However, the incidence of lung metastases was dramatically reduced. Furthermore, SNAI2 was required for proper postlactational involution of the breast. At 3 days post lactational involution, the mammary glands of Snai2-deficient mice exhibited lower levels of pSTAT3 and higher levels of pAKT1, resulting in decreased apoptosis. Abundant noninvoluted ducts were still present at 30 days post lactation, with a greater number of residual ERBB2+ cells. These results suggest that this defect in involution leads to an increase in the number of susceptible target cells for transformation, to the recovery of the capacity to generate mammospheres and to an increase in the number of tumors. Our work demonstrates the participation of SNAI2 in the pathogenesis of luminal breast cancer, and reveals an unexpected connection between the processes of postlactational involution and breast tumorigenesis in Snai2-null mutant mice.

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  • 03 September 2015

    This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue.

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Acknowledgements

JP-L was partially supported by FEDER and MICINN (PLE2009-119, SAF2014-56989-R), Instituto de Salud Carlos III (PI07/0057, PI10/00328, PIE14/00066), Junta de Castilla y León (SAN673/SA26/08, SAN126/SA66/09, SA078A09, CSI034U13), the ‘Fundación Eugenio Rodríguez Pascual’, the ‘Fundación Inbiomed’ (Instituto Oncológico Obra Social de la Caja Guipozcoa-San Sebastian, Kutxa) and the ‘Fundación Sandra Ibarra de Solidaridad frente al Cáncer’. AC-M was supported by FIS (PI07/0057) and MICINN (PLE2009-119). SC-L was funded by a JAEdoc Fellowship (CSIC)/FSE. MMS-F and AB-G are funded by fellowships from the Junta de Castilla y Leon. J-HM was supported by the National Institutes of Health, a National Cancer Institute Grant (R01 CA116481) and the Low-Dose Scientific Focus Area, Office of Biological and Environmental Research, US Department of Energy (DE-AC02-05CH11231). We thank Dr Montoliú for HC11 cells, Dr García Macías and the Comparative Pathology Core Facility of the ‘Centro de Investigación del Cáncer (CIC) de la Universidad de Salamanca’ for Pathology support, María Luz Hernández Mulas and Isabel Ramos for technical assistance, Dr Sánchez-García and Dr Martin-Zanca for useful comments along this project, Dr Balmain and Dr Lazo for comments about the manuscript and Nicholas Skinner for his useful help in English editing.

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Author notes

  1. L Hontecillas-Prieto

    Present address: 9Current address: Departamento de Patología Molecular, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.,

  2. A Castellanos-Martín

    Present address: 12Current address: Institute for Research in Biomedicine (IRB), Barcelona, Spain.,

  3. S Castillo-Lluva and L Hontecillas-Prieto: These authors contributed equally to this work as first authors and are listed in alphabetical order of surnames.

  4. A Blanco-Gómez and M del Mar Sáez-Freire: These authors contributed equally to this work as second authors and are listed in alphabetical order of surnames.

  5. A Castellanos-Martín and J Pérez-Losada: These authors contributed equally to this work as senior authors.

Authors and Affiliations

  1. Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain

    S Castillo-Lluva, L Hontecillas-Prieto, A Blanco-Gómez, M del Mar Sáez-Freire, M Pérez-Andrés, A Orfao, A Castellanos-Martín & J Pérez-Losada

  2. Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain

    S Castillo-Lluva, L Hontecillas-Prieto, A Blanco-Gómez, M del Mar Sáez-Freire, B García-Cenador, J García-Criado, M Pérez-Andrés, A Orfao, A Castellanos-Martín & J Pérez-Losada

  3. Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain

    B García-Cenador & J García-Criado

  4. Unidad de Citometría de flujo, Universidad de Salamanca, IBSAL, Salamanca, Spain

    M Pérez-Andrés & A Orfao

  5. Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain

    M Cañamero

  6. Life Sciences Division, Lawrence Berkeley National Laboratory (LBNL), University of California, Berkeley, Berkeley, CA, USA

    J H Mao

  7. Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA

    T Gridley

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  1. S Castillo-Lluva
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Castillo-Lluva, S., Hontecillas-Prieto, L., Blanco-Gómez, A. et al. A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development. Oncogene 34, 4777–4790 (2015). https://doi.org/10.1038/onc.2015.224

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