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Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer

Oncogene volume 32, pages 1428–1440 (2013)Cite this article

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Abstract

Basal-like breast cancer is an aggressive subtype of mammary carcinoma. Despite expressing basal markers, typical of mammary stem cells, this tumor has been proposed to originate from luminal progenitors, which are downstream of stem cells along the mammary epithelial hierarchy. This suggests that committed luminal progenitors may reacquire basal, stem-like characteristics, but the mechanisms that regulate this transition remain unclear. Using mouse models, we found that luminal progenitors express high levels of the Met receptor for hepatocyte growth factor (HGF), as compared with the other mammary epithelial sub-populations. Constitutive activation of Met led luminal progenitors to attain stem cell properties, including enhanced clonogenic activity in vitro and de novo ability to reconstitute mammary glands in repopulation assays in vivo. Moreover, in response to Met signaling, luminal progenitors gave rise to hyperplastic ductal morphogenesis and preferentially underwent basal lineage commitment at the expense of luminal cell-fate specification. Opposite and symmetric results were produced by systemic pharmacological inhibition of Met. Hence, Met signaling targets luminal progenitors for expansion, impairs their differentiation toward the mature luminal phenotype and enables their commitment toward the basal lineage. These results emphasize a critical role for Met in promoting deregulated proliferation and basal plasticity of normal luminal progenitors in the mammary gland, a complex of events that may be required for sustaining the functional and phenotypic properties of basal-like breast tumors.

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Acknowledgements

We thank Erica Lantelme for help with FACS sorting; Noemi Cavalera, Claudio Isella, Howard Kendrick, Simonetta Leto, Barbara Lupo, Paolo Luraghi, Fiona-Ann Magnay, Barbara Martinoglio, Enzo Medico, Roberta Porporato and Eugenia Zanella for help with experiments, discussion and sharing reagents; Fabrizio Maina, Laura Tarditi and Tuti Werdiningsih for animal husbandry; Raffaella Albano, Stefania Giove and Laura Palmas for technical assistance; Antonella Cignetto, Daniela Gramaglia and Francesca Natale for secretarial assistance. This work was supported by AIRC, Associazione Italiana per la Ricerca sul Cancro (IG project 10116 to LT); MIUR-FIRB, Fondo per gli Investimenti della Ricerca di Base – Futuro in Ricerca (AB); FPRC, Fondazione Piemontese per la Ricerca sul Cancro (LT); Breakthrough Breast Cancer and United Kingdom National Health Service funding to the National Institute for Health Research Biomedical Research Centre (MJS).

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Author notes

  1. S Gastaldi

    Present address: 8Current address: Massachusetts General Hospital, Cutaneous Biology Research Center, Charlestown, MA 02129, USA.,

  2. M J Smalley

    Present address: 9Current address: European Cancer Stem Cell Research Institute, Cardiff CF10 3AX, UK.,

  3. A Bertotti and L Trusolino: These authors share senior authorship.

  4. Department of Veterinary Morphophysiology, University of Torino School of Veterinary Medicine, Grugliasco, Italy

Authors and Affiliations

  1. Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), Candiolo, Italy

    S Gastaldi, F Sassi, D Torti, F Galimi, G Migliardi, A Bertotti & L Trusolino

  2. Department of Oncological Sciences, University of Torino School of Medicine, Candiolo, Italy

    S Gastaldi, G Migliardi, P M Comoglio, C Boccaccio, A Bertotti & L Trusolino

  3. The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK

    F Sassi, D Torti, G Molyneux & M J Smalley

  4. Janssen Research and Development, Beerse, Belgium

    P Accornero & T Perera

  5. Division of Molecular Clinical Oncology, Institute for Cancer Research and Treatment (IRCC), Candiolo, Italy

    P M Comoglio

  6. Laboratory of Cancer Stem Cell Biology, Institute for Cancer Research and Treatment (IRCC), Candiolo, Italy

    C Boccaccio

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T Perera is an employee of Janssen pharmaceutical companies of Johnson & Johnson. PM Comoglio receives research grants from Janssen pharmaceutical companies. The other authors declare no potential conflicts of interest.

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Gastaldi, S., Sassi, F., Accornero, P. et al. Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer. Oncogene 32, 1428–1440 (2013). https://doi.org/10.1038/onc.2012.154

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