This study has shown that serum levels of 25(OH)D were markedly higher and that PTH levels were considerably lower in patients with early‐stage breast cancer than in those with locally advanced or metastatic disease. The notably higher serum PTH in patients with metastatic disease than that in those with early‐stage disease is presumably due to the lower vitamin D level, resulting in a lower serum calcium and therefore a rise in serum PTH. The raised PTH level can therefore account for the lack of any difference in serum calcium between these two groups. Epidemiological studies have previously shown that maintenance of adequate levels of vitamin D via exposure to sunlight is associated with a reduced incidence and mortality of breast cancer.8,9,11
This may reflect the fundamental importance of vitamin D in regulating aspects of cellular behaviour such as cell growth. This is supported by in vitro data in breast cancer cell lines, as well as in vivo animal studies,6,7
which have shown the ability of 1,25(OH)2
D3 to inhibit proliferation and promote differentiation and apoptosis.1,2,3,4
In addition, an observational study showed lower levels of 1,25(OH)2
D3 in women diagnosed with primary breast cancer compared with a healthy cohort,11
and a decrease in vitamin D in patients with breast cancer with bone metastasis that progressed.14
The results of this study showing lower levels of 25(OH)D in women with advanced breast cancer lends weight to the hypothesis that the growth of breast cancer in vivo is inhibited by vitamin D. The exact reason for the deranged and low 25(OH)D levels in patients with advanced cancer as compared with those with early‐stage breast cancer is unclear, and also whether the decrease in 25(OH)D is causative for the advanced disease or is a direct consequence of the advanced disease as a result of cancer‐related reduced dietary intake or altered synthesis in the skin due to reduced sun exposure.
24‐Hydroxylase inactivates 1,25(OH)3
and is involved in the homeostasis of serum levels of 1,25(OH)3
, and it is suggested to be an oncogene.16
The expression of 24‐hydroxylase is shown to be higher in primary breast tumours than in normal breast tissue,17
and the levels of 1,24,25(OH)3
were considerably higher in malignant breast tumours. It is also known that 1,24,25(OH)3
does not induce an antiproliferative response in breast cancer cell lines. This can be reversed by antisense inhibition of 24‐hydroxylase in vitro.17
Therefore, a resistance mechanism to the potential effects of vitamin D—namely, via the dysregulation of 24‐hydroxylase activity—seems to exist in breast tumours. How this dysregulation differs between early‐stage and locally advanced or metastatic breast cancer is not known, given the previously normal tissue was compared with primary breast tumours.17
Possibly, in advanced breast cancer, a further dysregulation in the metabolism of vitamin D may result from some paracrine tumour effect, or tumours that have high 24‐hydroxylase levels may have a greater propensity to progress to advanced stage disease.
Vitamin D binds to the vitamin D receptor, which is a ligand‐activated transcription factor that controls gene transcription via binding to vitamin D response elements in DNA. Microarray analysis has shown that several key genes are up regulated or down regulated as a result of vitamin D treatment. One such key gene that is up regulated is the cyclin‐dependent kinase inhibitor p21, which has an important role in controlling cell cycle progression.18
Whatever the cause for the change in vitamin D levels, it can potentially have a marked effect on gene transcription and therefore on cellular phenotype. Lower serum vitamin D levels might therefore have some causative role in the progression from early‐stage to advanced disease as a result of altered gene transcription.
- Epidemiological studies, as well as in vitro and in vivo data, suggest a role for vitamin D in the pathogenesis of breast cancer.
- Vitamin D levels have been shown to be higher in normal women compared with those who have primary breast cancer, and decrease with the progression of bone metastases.
- This study shows a significantly higher level of 25‐hydroxyvitamin D in women with early breast cancer compared with those with advanced disease. Further work is required to determine the precise mechanism for the dysregulation of vitamin D levels in advanced breast cancer.
In summary, these findings lend support to the hypothesis that vitamin D has a role in the pathogenesis and progression of breast cancer. This report, while being an observational study, clearly shows that circulating vitamin D levels are lower in patients with advanced breast cancer than in those with early breast cancer. However, several questions remain unanswered. These include the potential causes and mechanisms underlying this dysregulation of vitamin D regulation, their precise molecular consequences and the potential clinical implications of monitoring or maintaining high circulating vitamin D levels in patients diagnosed with breast cancer. Answering these questions offers the potential of improving the risk stratification, surveillance and treatment of women with breast cancer.