title: A new role of SNAI2 in postlactational involution of the mammary gland links it to luminal breast cancer development.
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.
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Castillo-Lluva
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Hontecillas-Prieto
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Blanco-Gómez
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Del Mar Sáez-Freire
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.|Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
authors.forename: B
authors.initials: B
authors.lastname: García-Cenador
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.|Departamento de Cirugía, Universidad de Salamanca, Salamanca, Spain.
authors.forename: J
authors.initials: J
authors.lastname: García-Criado
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.|Unidad de Citometría de flujo, Universidad de Salamanca, IBSAL, Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pérez-Andrés
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.|Unidad de Citometría de flujo, Universidad de Salamanca, IBSAL, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Orfao
authors.affiliation: Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Cañamero
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory (LBNL), University of California, Berkeley, Berkeley, CA, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Mao
authors.affiliation: Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME, USA.
authors.forename: T
authors.initials: T
authors.lastname: Gridley
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Castellanos-Martín
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer (IBMCC), Universidad de Salamanca/CSIC, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Pérez-Losada
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis; D002352:Carrier Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007774:Lactation / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C498804:Erbb2ip protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C000604408:SNAI2 protein, human; D050796:STAT3 Transcription Factor; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; C494087:Stat3 protein, mouse; D014157:Transcription Factors; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt