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Osteocytic connexin hemichannels suppress breast cancer growth and bone metastasis

Oncogene volume 35, pages 5597–5607 (2016)Cite this article

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Abstract

Although the skeleton is one of the predominant sites for breast cancer metastasis, why breast cancer cells often become dormant after homing to bone is not well understood. Here, we reported an intrinsic self-defense mechanism of bone cells against breast cancer cells: a critical role of connexin (Cx) 43 hemichannels in osteocytes in the suppression of breast cancer bone metastasis. Cx43 hemichannels allow passage of small molecules between the intracellular and extracellular environments. The treatment of bisphosphonate drugs, either alendronate (ALN) or zoledronic acid (ZOL), opened Cx43 hemichannels in osteocytes. Conditioned media (CM) collected from MLO-Y4 osteocyte cells treated with bisphosphonates inhibited the anchorage-independent growth, migration and invasion of MDA-MB-231 human breast cancer cells and Py8119 mouse mammary carcinoma cells, and this inhibitory effect was attenuated with Cx43(E2), a specific hemichannel-blocking antibody. The opening of osteocytic Cx43 hemichannels by mechanical stimulation had similar inhibitory effects on breast cancer cells and this inhibition was attenuated by Cx43(E2) antibody as well. These inhibitory effects on cancer cells were mediated by ATP released from osteocyte Cx43 hemichannels. Furthermore, both Cx43 osteocyte-specific knockout mice and osteocyte-specific Δ130-136 transgenic mice with impaired Cx43 gap junctions and hemichannels showed significantly increased tumor growth and attenuated the inhibitory effect of ZOL. However, R76W transgenic mice with functional hemichannels but not gap junctions in osteocytes did not display a significant difference. Together, our studies establish the specific inhibitory role of osteocytic Cx43 hemichannels, and exploiting the activity of this channel could serve as a de novo therapeutic strategy.

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Acknowledgements

We thank Hongyun Cheng for technical assistance, Dr Lesley Ellies at the University of California at San Diego for providing Py8119 cells, Dr Lynda Bonewald at the University of Missouri at Kansas City for MLO-Y4 osteocytic cells, Dr Stephen Harris at UTHSCSA for 10-kb dentin matrix protein 1 (DMP1)-Cre mice and Dr Klaus Willecke at the University of Bonn and Dr Roberto Civitelli for mice with floxed Cx43 gene. The work was supported by Welch Foundation grant AQ-1507 and NIH grant EY012085 to JXJ, ES022057 to LZS and the NCI Cancer Center grant 2 P30 CA054174-17 to Cancer Therapy and Research Center.

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  1. Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX, USA

    J Z Zhou, M A Riquelme, S Gu, R Kar, X Gao & J X Jiang

  2. Department of Cellular and Structural Biology, San Antonio, TX, USA

    L Sun

  3. Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, TX, USA

    L Sun & J X Jiang

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Correspondence to J X Jiang.

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Zhou, J., Riquelme, M., Gu, S. et al. Osteocytic connexin hemichannels suppress breast cancer growth and bone metastasis. Oncogene 35, 5597–5607 (2016). https://doi.org/10.1038/onc.2016.101

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