Vitamin D Deficiency Linked With Poor Breast Cancer Outcomes

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In the study, which was published in the JournalEndocrinology,vitamin D was found to inhibit the InhiResebitor of differentiation 1 (ID1) gene in breast cancer tumors. Additionally, women were found to commonly have a preexisting vitamin D deficiency before the development of breast cancer. Previous studies have identified that theID1gene is commonly associated with activation of multiple tumor pathways and the development of primary tumors.²

"We found that ablation of vitamin D receptor expression within breast cancer cells accelerates primary tumor growth and enables the development of metastases, demonstrating a tumor autonomous effect of vitamin D signaling to suppress breast cancer metastases," said lead authors Jasmaine Williams, member of the Feldman Lab and cancer biology graduate student, and Abhishek Aggarwal, Postdoctoral Research Fellow, Endocrinology and Metabolism, in the study.

"We show that vitamin D signaling inhibits the expression of the tumor progression geneID1, and this pathway is abrogated in vitamin D deficiency in vivo in 2 murine models of breast cancer," Williams said.

Mice utilized in the 10-week study were split into 2 groups and were given either 500-IU vitamin D/kg diets or 25-IU vitamin D/kg diets. Breast cancer tumors were implanted into the left inguinal mammary fat pad and bioluminescent staining was employed to measure primary tumor growth once weekly, as well as lung, liver, and spleen metastases.

The livers in mice who received the low vitamin D produced a markedly lower amount of serum 25(OH)D compared with mice who received the higher amount of vitamin D. Those mice who became deficient in their 25(OH)D levels developed mammary tumors approximately 1 week earlier and had their primary tumor grow at a faster rate. Furthermore, deficient mice saw a significant increase in their tumor volume after 6 weeks, as compared with the non-deficient mice.

Metastases were also monitored in the mice, namely the breast cancer cell lines 168FARN and 4T1. Researchers found that cell line 4T1 had appreciably less vitamin D expression and metastasized in the mice, whereas 168FARN expressed much higher vitamin D levels and stayed local to the primary site of the tumor.

According to the Institute of Medicine (IOM),³women between the ages of 1 and 70 should receive 15 micrograms of vitamin D daily, or roughly 600 IU. Women over the age of 70 should have an intake of 20 micrograms daily, or 800 IU. The IOM does not have concrete recommendations for infants, though the institute does suggest that 10 micrograms daily, or 400 IU, would be sufficient.

"These findings are relevant to humans, because we discovered that the mechanism of VDR regulation ofID1is conserved in human breast cancer cells, and there is a negative correlation between serum 25-hydroxyvitamin D levels and the level ofID1in primary tumors from patients with breast cancer," said Williams et al.

Relevancy to human breast cancer was initially confirmed by the researchers through finding that calcitriol (1,25-dihydroxyvitamin D3), or what becomes 25(OH)D, downregulatedID1. VDR regulation also played a part in the development and metastases of the breast cancer tumors in mice, as it also does in humans.

“A number of epidemiological studies (but not all) indicate that there is an inverse correlation between the risk of developing breast cancer and serum 25(OH)D levels in humans. Further, biological studies suggest that pharmacologic levels of calcitriol inhibits cancer growth, particularly in tissue culture models," said Williams et al. "However, treatment with high-dose vitamin D likely has pharmacological effects that are distinct from the pathophysiology of vitamin D deficiency."

References

1. Williams J, Aggarwal A, Swami S, et al. Tumor Autonomous Effects of Vitamin D Deficiency Promote Breast Cancer Metastasis. Endocrinology. 2016:en.2015-2036. doi:10.1210/en.2015-2036.
2. Ling MT, et al. The multiple roles of Id-1 in cancer progression. - PubMed - NCBI.Ncbinlmnihgov. 2016. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17177845. Accessed March 8, 2016.
3. Vitamin D and Cancer Prevention. National Cancer Institute. 2016. Available at: http://www.cancer.gov/about-cancer/causes-prevention/risk/diet/vitamin-d-fact-sheet. Accessed March 8, 2016.