Artikel
Loss of the Vitamin D Receptor Promotes Human Breast Cancer Metastasis to Bone
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Veröffentlicht: | 10. Oktober 2016 |
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Gliederung
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Objectives: Breast cancer is amongst the most prevalent malignancies globally with up to 40% of patients developing skeletal metastases. We have previously demonstrated that vitamin D deficiency, partly through an increase in bone turnover, accelerates the growth of human breast cancer cells in rodent models of bone metastasis. The purpose of the current study was to define the role of the vitamin D receptor (VDR) in systemic breast cancer spread to bone.
Methods: VDR expression was knocked down in the human breast cancer cell line, MDA-MB-231 (MDAVDR-/-). Compared to non-target (NT) controls transfected with an empty vector, knockdown efficiency in MDAVDR-/- cells was ~80%. MDAVDR-/- and NT-cells were further transfected with a luciferase gene and injected into the left ventricle of female nude mice (n=11 for each, MDAVDR-/- and NT). Systemic cancer cell spread and tumour growth were monitored by sequential in vivo bioluminescent imaging (BLI), high resolution X-ray and µ-CT imaging for a period of 30 days. Affected bones were analysed by histomorphometry and immunohistochemistry at endpoint (day 30).
Results and Conclusion: Compared to NT controls, MDAVDR-/- cells were characterised by a significant increase in cell migration and cell invasion in vitro and a substantial reduction in E-cadherin mRNA expression levels. Mice injected intra-cardially with MDAVDR-/- cells developed more metastases at day 5 (p<0.01) and 10 (p=0.03), with light emission measurements generating significantly higher values at all time points in MDAVDR-/- mice compared to animals injected with NT-cells. After 20 days, multifocal metastases were detectable in all animals and tumours were visible on X-ray. Of note, mice injected with MDAVDR-/- cells had significantly larger bone lesions compared to control mice (P<0.01). Immunohistochemistry revealed significant down-regulation of E-cadherin in tumours derived from MDAVDR-/- cells compared to NT controls.
We conclude that silencing the VDR in human breast cancer cells boosts their systemic metastatic potential, resulting in significantly greater tumour burden. Our results clearly indicate that the VDR itself impacts breast cancer cell invasiveness and growth, likely via interaction with E-cadherin.