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Tumorigenesis

Joining the RANKs

Nature Reviews Cancer volume 10, pages 738–739 (2010)Cite this article

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Schramek, Leibbrandt and colleagues found that medroxyprogesterone acetate (MPA) — a commonly used progestin — substantially increased RANKL mRNA and protein expression in MECs. Treatment with MPA failed to induce the proliferation of MECs and the expansion of mammary stem cells in RANKΔmam mice (in which Tnfrsf11a (which encodes RANK) is ablated in MECs). MPA alone is not sufficient to induce mammary tumorigenesis, so it was combined with DMBA, but tumour onset was delayed in RANKΔmam mice, causing improved survival. The NF-κB pathway was not activated and cyclin D1 was not induced — both downstream effects of RANKL–RANK activation — in tumours from RANKΔmam mice. The deletion of conserved helix–loop–helix ubiquitous kinase (Chuk; which encodes the NF-κB pathway member IKKα) in MECs delayed the onset of MPA-driven mammary tumorigenesis in vivo, suggesting that activation of the NF-κB pathway is important for MPA-mediated tumorigenesis.

So, why is the DNA-damaging agent DMBA also necessary for MPA-induced tumorigenesis? The authors found that RANKL reduces the proportion of cells that undergo apoptosis in response to DNA damage. Similarly, treatment with MPA protected MECs from ionizing radiation-induced apoptosis, and this was dependent on the expression of RANKL and IKKα. Therefore, MPA-induced RANKL–RANK activation seems to provide a growth and survival advantage to damaged MECs.

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ORIGINAL RESEARCH PAPERS

  1. Schramek, D. et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 29 Sep 2010 (doi: 10.1038/nature09387)

  2. Gonzalez-Suarez, E. et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 29 Sep 2010 (doi: 10.1038/nature09495)

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Authors
  1. Gemma K. Alderton
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Alderton, G. Joining the RANKs. Nat Rev Cancer 10, 738–739 (2010). https://doi.org/10.1038/nrc2955

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