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Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease

Oncogene volume 30, pages 1681–1692 (2011)Cite this article

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Abstract

Gap junctions, the channels formed by the connexin (Cx) family of proteins, are responsible for direct intercellular communication. Although connexins are considered as tumor suppressors, their overall role in cancer onset, progression and metastasis is somewhat controversial. This study uses a novel Cx43 mutant mouse model (G60S mice) and cross-breeding strategies to determine the role of Cx43 in all stages of breast tumorigenesis. G60S mice were cross-bred with ErbB2 overexpressing mice, and spontaneous and 7,12-dimethylbenz[α]anthracene (DMBA)-induced tumor development was evaluated. Mice were killed when tumors reached ∼1 cm3 or when mice showed signs of critical illness. In both spontaneous and DMBA studies, onset of palpable tumors was delayed in G60S mice compared with mice in control groups. Moreover, while tumors from control mice reached the size threshold, most DMBA-exposed Cx43 mutant mice were killed prematurely because of labored breathing, independent of the presence of a palpable tumor. Reduced Cx43 levels in Cx43 mutant mice were accompanied by extensive mammary gland hyperplasia. Lung histology revealed that all Cx43 mutant mice exhibited mammaglobin-positive mammary gland metastases to the lung, and the number of metastases was increased by threefold in Cx43 mutant mice on treatment with DMBA. Thus, while reduced levels of Cx43 delayed the onset of palpable tumors, normal Cx43 levels inhibited mammary gland tumor metastasis to the lungs. Understanding the mechanisms of how Cx43, which is expressed primarily in myoepithelial cells, inhibits mammary gland tumor metastasis is critical as Cx43 is assessed as a candidate for therapeutic intervention.

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Acknowledgements

We thank David Goodale for his technical assistance. We are grateful to Dr Janet Rossant and team at the Centre for Modeling Human Disease (Toronto, ON, Canada) for providing the mouse model. This research was funded by the Canadian Breast Cancer Research Alliance to DWL, and by Fellowships from the Canadian Institutes of Health Research, the Canadian Institutes of Health Research Strategic Training Program and the Fonds de la Recherche en Santé du Quebec to IP. ALA is supported by a Canadian Institutes of Health Research New Investigator Award.

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada

    I Plante, A L Allan & D W Laird

  2. Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada

    M K G Stewart, K Barr & D W Laird

  3. Department of Oncology, University of Western Ontario, London, Ontario, Canada

    A L Allan

  4. London Regional Cancer Program, London, Ontario, Canada

    A L Allan

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Correspondence to D W Laird.

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Plante, I., Stewart, M., Barr, K. et al. Cx43 suppresses mammary tumor metastasis to the lung in a Cx43 mutant mouse model of human disease. Oncogene 30, 1681–1692 (2011). https://doi.org/10.1038/onc.2010.551

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