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Vitamin D

In recent years, vitamin D has been shown to decrease the risk of getting breast cancer. When different mechanisms of the vitamin D pathway are inhibited, breast cancer formation is favored. The two major forms of vitamin D, calcidiol and calcitriol, play a role in prevention. Vitamin D in the body can be measured by the serum concentration of calcidiol.

Mechanisms

Genes

Two important genes relating to the vitamin D pathway are CYP24A1 and CYP27B1. CYP24A1 is responsible for metabolizing both calicidiol and calcitriol. The other gene, CYP27B1, is responsible for converting calcidiol into the more active metabolite calcitriol. Both of the genes are responsible for the local concentration of vitamin D in the breast tissue. As the breast tumor progresses, the expression of CYP24A1 is increased whereas the expression of CYP27B1 is decreased. The result is that less calcidiol is converted to the active form and also that catabolism of vitamin D is increased. This result has detrimental effects on the cells in the breast tissue and favors tumor progression and formation.

Calcidiol and Calcitriol

Calcidiol is important in protecting breast cells against cellular stress. Cellular stress is implicated in starting the tumor process. Calcitriol, once bound to the vitamin D receptor, is involved with modulation of cell proliferation, differentiation, cancer metastasis and angiogenesis. The effective concentration of calcitriol for cell protection is 10nmol/L whereas the most effective concentration for calcidiol is 250nmol/L. The difference in effective concentrations is caused by how tightly the two ligands bind to the vitamin D receptor with calcitriol binding tighter to the vitamin D receptor.

Vitamin D Receptor

One of the most important parts of the vitamin D pathway is the vitamin D receptor (VDR). This receptor is a ligand regulated transcription factor that has several hundred direct target genes. The VDR is present in over thirty human tissues including the mammary gland. During glandular development, which occurs during puberty, pregnancy and involution, VDR expression is regulated. Two ligands that bind to the VDR are calcidiol and calcitriol. Once bound, the VDR protein levels start to increase because the ligands cause an increase in the transcription of the VDR gene. The increased protein levels correlate with an increase in the antitumor efficacy of the VDR. If the VDR is disrupted in any way, the cell’s ability to stop the progression of cancer is greatly inhibited favoring tumor growth. When a ligand is bound to the vitamin D receptor, it has an influence over cell cycling, proliferation, differentiation and apoptosis in the cells.

Case Studies

Many case studies have been performed to investigate the link between breast cancer and vitamin D. One of the main sources of vitamin D is from exposure to ultra violet B radiation. This exposure accounts for ninety percent of calcidiol in the body. Women who are exposed to more sunlight have a lower risk for advanced but not localized breast cancer. This effect is more prevalent in women with lighter skin pigmentation than in women with darker skin pigmentation because it is harder to measure the effect of UV exposure and vitamin D synthesis in darker pigmentation. A maximum of vitamin D production from UV exposure in light skin pigmentation is reached after a half hour of exposure, with darker skin pigmentation requiring a longer exposure time [6]. Many factors affect the amount of UV light that can be absorbed. These factors include environmental factors such as the latitude, altitude, season and time of day and personal factors such as skin pigmentation, age, clothing, and sunscreen use. An example of an environmental factor is that the mortality rates from breast cancer in the United States are higher in the Northeast than in the South. The Northeast has less solar radiation which causes a decrease in vitamin D production and a higher risk of breast cancer. If the maximum amount of vitamin D is obtained during adolescent development, a greater reduced risk of breast cancer is seen [3]. Adolescent development is a crucial time for breast development because during this time the mammary glands are regulating the expression of the VDR which is important in cell proliferation and differentiation. It has also been theorized that increased outdoor physical activity including picnics, walks outside, sports and other activities could reduce the risk of breast cancer [3]. Vitamin D can also be obtained exogenously through various foods such as fortified milk and fatty fish and also through other supplements. A study was performed to investigate milk consumption and the risk of breast cancer. It was found that there is an inverse correlation between milk consumption and breast cancer [3]. The study related women who drank ten glasses of milk a week with women who consumed no milk [3]. There is also an inverse correlation between reduced serum concentrations of vitamin D and incidence of breast cancer in post-menopausal women [4,5]. This correlation is complicated by menopausal hormone therapy and increasing number of pregnancies [5]. Women who have never used hormonal therapy or who have not had many pregnancies, show a stronger correlation of serum concentration to risk of breast cancer than women who have used hormonal therapy and who have had many pregnancies [5]. The correlation is also non-linear meaning that it is strongest in women with low serum concentration than in women with high serum concentrations [5]. A serum concentration of 52ng/mL of calcidiol is related to a fifty percent decrease in risk of breast cancer [6].