Vit D and Cancer  Cancer Gov
http://www.cancer.gov/cancertopics/factsheet/prevention/vitamin-D
       A large number of scientific studies of many types have provided evidence suggesting that vitamin D may have a role in cancer prevention. The first evidence came from epidemiologic studies known as geographic correlation studies. In these studies, an inverse relationship was found between sunlight exposure levels and the rates of incidence and death for certain cancers. Individuals living in southern latitudes were found to have lower rates of incidence and death for these cancers than those living at northern latitudes. Because sunlight/UV exposure is necessary for the production of vitamin D3, researchers hypothesized that differences in vitamin D levels accounted for the observed relationships.
      Evidence of a possible cancer-protective role for vitamin D was also found in laboratory studies of the effect of vitamin D treatment on cancer cells in culture. In these studies, vitamin D promoted the differentiation and death (apoptosis) of cancer cells, and it slowed their proliferation.

      Randomized clinical trials designed to investigate the effects of vitamin D intake on bone health have also provided evidence that higher vitamin D intakes may reduce the risk of cancer. One study involved nearly 1,200 healthy postmenopausal women who took daily supplements of calcium and vitamin D (28 μg vitamin D, or 1,100 IU, a relatively large dose) or a placebo for 4 years. The women who took the supplements had a 60 percent lower overall incidence of cancer (6); however, the study did not include a vitamin D-only group. Moreover, the primary outcome of the study was fracture incidence; it was not designed to measure cancer incidence. This limits the ability to draw conclusions about the effect of vitamin D intake on cancer incidence.

      A number of observational studies have been carried out to investigate the possibility that vitamin D reduces the risk of specific cancers, particularly colorectal cancer and breast cancer, but vitamin D's effects on prostate cancer and pancreatic cancer have also been examined. These studies have yielded inconsistent results, most likely because of the methodologic difficulties in conducting observational studies of dietary components (7). In these studies, information about dietary intakes is obtained from the participants through the use of food frequency questionnaires, diet records, or interviews in which the participants are asked to recall information about their dietary intakes. Information collected in this manner can be inaccurate. Other dietary components or energy balance may also modify vitamin D metabolism (8).

      Measuring serum levels of 25-hydroxyvitamin D to determine vitamin D status avoids some of the limitations of assessing dietary intake. However, vitamin D levels in the blood can vary seasonally and with the laboratory technique used to measure them. These variations complicate the interpretation of studies that measure the concentration of vitamin D in serum at a single point in time.

      Finally, it is difficult to separate the effects of vitamin D and calcium because of the complicated biological interactions between these micronutrients. To fully understand the effect of vitamin D on cancer and other health outcomes, new randomized trials will need to be carried out (9). However, the appropriate dose of vitamin D to use in such trials is still not clear (10).
   7. Is there evidence that vitamin D can help reduce the risk of colorectal cancer?

      Epidemiologic studies of the association between vitamin D and the risk of colorectal cancer have provided some indications that higher levels of intake are associated with a reduced risk. However, the data are inconsistent.

      In the American Cancer Society's Cancer Prevention Study (CPS) II Nutrition Cohort, the diet, medical history, and lifestyle of more than 120,000 men and women were analyzed (11). Men who had the highest intakes of vitamin D through both their diet and supplement use (greater than 13 μg, or 525 IU, per day) had a slightly lower risk of colorectal cancer than men who had the lowest vitamin D intakes. However, this association was not observed among women.

      In a pooled analysis of data from 10 cohort studies (including the CPS II cohort), individuals with the highest dietary vitamin D intakes had a slightly lower risk of colorectal cancer than those with the lowest intakes, but the reduction in risk was not statistically significant (12).

      In the Women's Health Initiative randomized trial, healthy postmenopausal women took daily supplements that contained both calcium and 10 μg (400 IU) vitamin D or a placebo for an average of 7 years. Supplementation did not reduce the incidence of colorectal cancer (13). However, some scientists have raised the possibility that the relatively low level of vitamin D supplementation and the short duration of participant follow-up might account for the negative results.

      At least one epidemiologic study has reported an association between vitamin D and reduced mortality from colorectal cancer. Among the 16,818 participants in the Third National Health and Nutrition Examination Survey, those with higher vitamin D blood levels (≥ 80 nmol/L) had a 72 percent lower risk of colorectal cancer death than those with lower vitamin D blood levels (< 50 nmol/L) (14).

      Most colorectal cancers develop from pre-existing colorectal adenomas, and interventions that reduce the risk of adenoma development or recurrence are likely to reduce the risk of colorectal cancer. Several large studies have investigated the association of vitamin D intake or serum status with adenoma risk.

      A cohort from the National Cancer Institute (NCI)-sponsored Polyp Prevention Trial (PPT) was evaluated for the association of vitamin D intake with recurrence of colorectal adenomas in individuals who previously had one or more adenomas removed during a qualifying colonoscopy (15). PPT was a multicenter randomized clinical trial to determine the effects of a diet high in fiber, fruits, and vegetables and low in fat on adenoma recurrence. The detailed dietary information obtained during the trial allowed the researchers to investigate the association between additional dietary factors and adenoma recurrence. Total vitamin D intake (that is, from dietary sources and supplements combined) was not associated with a reduced risk of adenoma recurrence (15). However, individuals who used any amount of vitamin D supplements had a lower risk of adenoma recurrence (15).

      In another study, the vitamin D intakes of 3,000 people from several Veterans Affairs medical centers were examined to determine whether there was an association between intake and advanced colorectal neoplasia (an outcome that included high-risk adenomas as well as colon cancer) (16). Individuals with the highest vitamin D intakes (more than 16 μg, or 645 IU, per day) had a lower risk of developing advanced neoplasia than those with lower intakes (16).

      A pooled analysis of data from these and a number of other observational studies found that higher circulating levels of vitamin D and higher vitamin D intakes were associated with lower risks of colorectal adenoma (17). Inverse associations were seen with both dietary and total vitamin D intake but not with supplemental vitamin D intake. However, the associations with dietary intake were not statistically significant.

      Another large, NCI-sponsored randomized, placebo-controlled trial explored the effects of calcium supplementation and blood levels of vitamin D on adenoma recurrence (18). Calcium supplementation reduced the risk of adenoma recurrence only in individuals with vitamin D blood levels above 73 nmol/L. Among individuals with vitamin D levels at or below this level, calcium supplementation was not associated with a reduced risk (18).
   8. Is there evidence that vitamin D can help reduce breast cancer risk?

      As with colorectal cancer, epidemiologic studies of the association between vitamin D and breast cancer risk have had conflicting results. Although several studies have suggested an inverse association between vitamin D intake and the risk of breast cancer, others have shown no association or even a positive association (that is, individuals with higher intakes had higher risks). A meta-analysis of six studies that investigated the relationship between vitamin D intake and breast cancer risk found no association (19). However, most women in these studies had relatively low vitamin D intakes, and, when the analysis was restricted to women with the highest vitamin D intakes (>10 μg, or 400 IU, per day), their breast cancer risks were lower than those of women with the lowest intakes (typically < 1.25 μg, or 50 IU, per day) (19).

      In the Women's Health Initiative randomized trial of calcium plus vitamin D supplementation, supplement use for an average of 7 years did not reduce the incidence of invasive breast cancer compared with placebo (20).

      The association between blood levels of vitamin D and breast cancer risk was examined in a cohort of postmenopausal women who were enrolled in NCI's Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and from whom blood was drawn at study entry. During the subsequent follow-up period, 1,005 of these women developed breast cancer. When researchers compared the blood vitamin D levels of these women with those of 1,005 similar control women who did not develop breast cancer, they found no association between vitamin D status and risk of breast cancer (21).
   9. Is there evidence that vitamin D can help reduce prostate cancer risk?

      Some geographic correlation studies (see Question 6) have suggested that men exposed to higher levels of sunlight may have a lower risk of prostate cancer. Although some epidemiologic studies have suggested that higher vitamin D levels are associated with increased prostate cancer risk, most studies have not shown such an association.

      In one relatively large study of men diagnosed 1 to 8 years after their blood was drawn, an increase in vitamin D blood levels was not associated with decreased risk of prostate cancer overall (20). Indeed, there was some evidence that men with higher vitamin D levels had an increased risk for aggressive disease (22).

      In another study, the European Prospective Investigation into Cancer and Nutrition (EPIC), blood samples obtained at study entry were examined for 652 men who developed prostate cancer during follow-up and 752 matched control subjects (23). No association was observed between serum vitamin D levels and risk of prostate cancer, either overall or by cancer stage.
  10. Is there evidence that vitamin D can help reduce pancreatic cancer risk?

      Participants in the Health Professionals Follow-Up Study and the Nurses' Health Study (more than 120,000 total), who provided detailed information on their diet through questionnaires at study entry, were followed for 16 years for the incidence of pancreatic cancer, and 365 cases were identified. Compared with participants with the lowest vitamin D intakes, those with higher intakes had progressively lower risks of pancreatic cancer (24). In contrast, among Finnish male smokers participating in the Alpha-Tocopherol, Beta-Carotene (ATBC) study (25), higher serum levels of vitamin D were associated with an increased risk of pancreatic cancer.

      In a study conducted among a large cohort of individuals aged 55 to 74 who were enrolled in the PLCO Screening Trial, vitamin D levels in blood samples obtained at study entry were compared among 184 individuals diagnosed with pancreatic cancer during nearly 12 years of follow-up and 368 matched cancer-free control subjects (26). No association between vitamin D level and pancreatic cancer incidence was observed.
  11. What are the possible mechanisms by which vitamin D may modify cancer risk?

      Mechanisms by which vitamin D may modify cancer risk are not fully understood. Laboratory studies have shown that vitamin D promotes cellular differentiation, decreases cancer cell growth, and stimulates apoptosis (27, 28).

      Vitamin D acts on cells by binding to the vitamin D receptor (VDR). The VDR is a regulator of gene transcription that is found in the nucleus of cells. Vitamin D-bound VDR binds to the retinoid-X receptor (RXR), and the resulting complex activates the expression of specific genes. Among the many genes regulated by vitamin D are those that produce the proteins calbindin and TPRV6, both of which are involved in the absorption of calcium by intestinal cells (29). Another vitamin D-regulated gene is CYP3A4, whose protein product detoxifies the bile acid lithocholic acid (LCA). LCA is believed to damage the DNA of intestinal cells and may promote colon carcinogenesis. Stimulating the production of a detoxifying enzyme by vitamin D could explain a protective role for vitamin D against colon cancer (30).
      Further insight into the mechanisms by which vitamin D might modify cancer risk could come from study of the vitamin D receptor itself. A large number of variant forms of the VDR gene have been identified, some of which are known to alter the structure or function of the VDR protein. Some of these variants have been linked to risk for certain cancers, including prostate, colorectal, breast, bladder, and melanoma (31). The association of VDR variants with cancer risk differs by cancer site and appears to be modified by environmental exposures, such as diet and sun exposure.

  12. How can people get enough sunlight for vitamin D synthesis while minimizing the risk of skin cancer?

      Although people obtain some vitamin D from dietary sources, most vitamin D is made in the body after the skin is exposed to sunlight. Despite the known and potential health benefits of vitamin D, increasing sun exposure increases the risk of skin cancer. In general, most experts believe that people should continue to use sun protection when UV levels are moderate or higher. Some researchers have suggested that brief daily exposure to UV will ensure adequate vitamin D production, but many variables (such as skin color, latitude, and season) can affect the production of vitamin D, and such recommendations have proven controversial. Other experts recommend vitamin D supplementation to avoid the problem of increasing skin cancer risk.
  13. Does NCI recommend the use of vitamin D supplements to prevent colorectal or other cancers?

      No. Although some evidence suggests that vitamin D may provide some protection against colorectal and possibly other cancers, the evidence of potential benefit is limited and inconsistent. Therefore, NCI does not recommend the use of vitamin D supplements to reduce the risk of colorectal or any other type of cancer.

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