Deprivation of the vitamin D receptor (VDR) fuels breast cancer metastases to bone
05 March 2019 (online)
We have recently demonstrated in a murine model of bone metastases that loss of the vitamin D receptor (VDR) increases the metastatic potential of human breast cancer cells to bone through enhanced epithelial to mesenchymal transition (EMT). The aim of the current study was to analyse primary and secondary cancer tissue samples of patients with breast cancers that developed bone metastases over the course of the disease.
Tissue samples of 15 patients that developed metastatic bone disease following breast cancer were analysed histologically using H&E staining and immunohistochemistry (IHC) for GATA3&CAM5.2 (tumour-specific) and VDR expression. Of note, primary tumour samples and the subsequent metastasis in bone were analysed and compared for every patient. All samples were scored independently and blindly. Tumours were identified and VDR expression was graded following an established scoring system comprising the assessment for intensity of VDR staining as well as the percentage of tumour cells stained.
Upon examination of primary breast cancer tissue and bone metastases, we found that overall VDR expression was significantly lower in bone metastases compared to primary tumour samples. Specifically, compared to primary counterparts (breast), the intensity of VDR staining and the percentage of tumour cells stained within bone metastases were significantly lower (p < 0.0001 for both).
Together with our findings from pre-clinical studies, we propose that loss of the VDR in breast cancer cells defines a critical turning point in oncogenesis that accelerates cancer cell dissemination resulting in an increased susceptibility for bone metastases. Our research may help to explain the inconsistencies in the associations between vitamin D levels and tumour outcomes found in clinical studies, as the effects of vitamin D on tumour behaviour are likely to depend on VDR status. Further, it has previously been demonstrated that VDR expression is regulated by a number of different promoter elements and transcription factors. Moreover, is has been shown that VDR expression is correlated with RXR, HDAC2 and HDAC8 expression which might also contribute to alterations in the migratory potential of breast cancer cells. Hence, future research into the regulatory pathways that may be responsible for decreased VDR expression is indispensable.