Vitamin D regulates the flow of calcium into the bloodstream and is crucial for normal bone development. Vitamin D also has a role in regulating parathyroid, neuromuscular, immune, and insulin functions. Vitamin D has been found to be associated with lower risks of cardiovascular disease and age-related cognitive impairment, as well as Hodgkin’s and non-Hodgkin’s lymphoma and esophageal, lung, pancreatic, renal, colorectal, endometrial, prostate and ovarian cancer.
Vitamin D binds to the vitamin D receptor
Vitamin D influences breast cancer development and progression in important ways, but the relationship is not fully understood. Vitamin D influences the expression of breast cancer-related gene activity, including cell differentiation, cell growth, and angiogenesis, all of which are related to cancer development and progression.
Vitamin D binds to the vitamin D receptor (VDR). The impact of vitamin D on breast cancer is influenced by VDR genotype; women can have one of several variants in the VDR gene and these gene polymorphisms influence the potential anticarcinogenic effects of vitamin D. The effect of vitamin D on breast cancer risk is also modified by the level of calcium consumed since various combinations of calcium and vitamin D can have differing effects on cellular proliferation and differentiation. One study found that certain VDR genotypes are associated with lower risk of breast cancer in women consuming high levels of calcium. In addition, vitamin D has been shown to inhibit the growth of tamoxifen-resistant breast cancer cells in the laboratory, possibly through a VDR-related mechanism.
Measuring vitamin D intake is not straightforward
Intake of vitamin D can be difficult to assess since the vitamin is produced in the skin as well as being a component of some foods. The level of vitamin D in the blood is not necessarily proportionate to the levels in other tissues such as the breast. In addition, it appears that vitamin D may be more influential in protecting against breast cancer when consumed early in life. For these and others reasons, not all population studies have found an association between vitamin D intake or plasma vitamin D and breast cancer.
Forms of vitamin D
Generally speaking, “vitamin D” refers to a set of fat-soluble prosteroids and their metabolites. Vitamin D3 (cholecalciferol) is the form most useful to human beings. Vitamin D3 is made in the skin when skin is exposed to sunlight (when the UV index is at least 3). Although some vitamin D supplements contain vitamin D2 (ergocalciferol), it makes more sense to take vitamin D3 since Vitamin D2 is not produced by vertebrates. Whether obtained from sun exposure to the skin, food, or supplements, vitamin D must undergo chemical reactions to become calcitriol (1,25-Dihydroxycholecalciferol) and become useable in the body. The blood test for vitamin D measures the level of 25-hydroxyvitamin D (25(OH)D, 25OHD, 25-OH-D or 25-OHD), which is the primary metabolic product of vitamin D3 in the blood. In this web page, by “vitamin D,” we mean vitamin D3 and its metabolites unless otherwise stated.
Vitamin D and risk of breast cancer diagnosis
Numerous studies have examined the association between vitamin D and risk of breast cancer. Most, but not all, have found that low levels of vitamin D increase risk of breast cancer whereas higher levels are protective.
- Two 2018 studies reported a reduced risk of breast cancer among women with the highest vitamin D exposure, however this appeared to be confined to premenopausal women in the one study that took menopausal status into account.
- Another study reported that women at high risk for breast cancer taking 2000 IU vitamin D daily experienced a 20% increase in a tumor promoting prostaglandin (PGE2) in their nipple fluid. Normal-risk women did not experience this increase. There was no significant change in circulating levels of PGE2.
- A study with U.S. and Swedish participants found an association between high circulating vitamin D levels and reduced breast cancer risk only in premenopausal women.
- A Japanese study found a reduced risk of breast cancer among women with the highest quartile of vitamin D intake, however this inverse association was confined to premenopausal women.
- A meta-analysis of 11 case-control studies reported that a serum 25(OH)D level of 47 ng/ml was associated with a 50% lower risk of breast cancer. A 2009 meta-analysis of 36 studies also concluded that there was a significant inverse relationship between vitamin D intake and risk of breast cancer. In addition, the study reported a significant decrease in risk of breast cancer for those with the highest calcium consumption.
- A large Swedish prospective study found no significant relationship between risk of breast cancer and sun exposure variables, including annual number of sunburns, skin sun sensitivity, time spent on sunbathing vacations, or solarium use at any age of exposure. There was also no association found between breast cancer incidence and dietary vitamin D intake or supplementary multivitamin use.
- A Canadian case-control study found that while vitamin D intake was most strongly associated with lower risk of hormone receptor positive (ER+/PR+) breast cancer, it also appeared to be associated with lower risks of hormone receptor negative (ER-/PR-) and mixed receptor status (ER+/PR-) tumors.
- A U.S. study reported that breast cancer patients with suboptimal levels (under 32 ng/mL) of vitamin D were three times more likely to develop triple negative (ER-/PR-/HER2-) breast cancer than patients with optimal levels. In other words, low vitamin D appears to increase the aggressiveness of breast cancer that develops.
- An Italian study found that risk of breast cancer was significantly lower for women in the top three tenths of vitamin D intake than those in the bottom three tenths. In fact, no protection was found for vitamin D up to the seventh decile of intake. The inverse association between high intake of vitamin D and breast cancer was consistent regardless of menopausal status.
- A Chinese case-control study reported that breast cancer patients were more likely to be severely vitamin D deficient than cancer-free women. A significant dose-response was found, with women in the highest quintile of vitamin D having the lowest risk of breast cancer and those in the lowest quintile having the highest risk.
- A study of women with at least one first degree or second degree relative with breast or ovarian cancer found that breast density was inversely associated with vitamin D intake. High breast density has been found to be associated with increased risk of breast cancer.
- A Canadian case-control study found that increasing sun exposure during ages 10 to 19 was associated with lower subsequent risk of breast cancer. Reduced risk was also found for cod liver oil consumption and increasing milk intake.
Vitamin D during breast cancer treatment
Levels of vitamin D normally drop during chemotherapy, however this decline is not in itself associated with worse prognosis. Vitamin D supplementation during chemotherapy can raise circulating vitamin D levels and this appears to enhance the treatment effects. The long-term impact on prognosis of taking vitamin D during treatment appears to be favorable:
- A 2020 review reported that vitamin D is able to help overcome the molecular mechanisms of drug resistance in addition to enhancing the effects of traditional cancer chemotherapy.
- An Irish study reported that breast cancer-specific mortality was 20% lower in women with new post-diagnosis vitamin D prescriptions than those without such prescriptions. The death rate was 49% lower if vitamin D was initiated within six months of breast cancer diagnosis.
- Over two-thirds of breast cancer patients in one study were found to be vitamin D deficient. Generally speaking, deficiency was higher in non-white patients and patients with later-stage disease. High-dose vitamin D supplementation (at least 50000 IU weekly) resulted in a greater increase in plasma vitamin D (+28 ng/mL; p< 0.01) than low-dose vitamin D (+7 ng/mL; p=0.03) or no supplementation (+2 ng/mL). The authors concluded that conventional low-dose vitamin D was not effective.
- In a laboratory study, vitamin D3 was found to increase breast cancer cell death caused by radiotherapy from approximately 30% to 75%.
- A large Norwegian population study found significant variations in long-term prognosis by season of diagnosis of breast, colon and prostate cancer. The lowest risks of cancer death were associated with diagnoses that had been made during the summer and fall, the seasons with the highest levels of vitamin D3. The authors concluded that a relatively high level of vitamin D3 at the time of diagnosis, and therefore, during cancer treatment, may improve prognosis of the three cancer types studied.
- A phase 2 trial of daily 10000 IU vitamin D supplementation in women with bone metastases found that the vitamin D did not influence bone resorption or reduce pain overall. However, a reduction in the number of pain sites was observed and the treatment reduced elevated parathyroid hormone levels, which presumably had been caused by long-term bisphosphonate use.
Based on the available evidence to date, it is acceptable to take vitamin D supplements during most breast cancer treatment.
Vitamin D and risk of breast cancer recurrence or metastasis
Does a vitamin D deficiency at diagnosis predict recurrence? Once a woman has been diagnosed with breast cancer, is there a benefit to increasing the level of circulating vitamin D? Does vitamin D supplementation during and after treatment affect long-term prognosis? A few studies have attempted to answer these questions:
- A large 2020 study reported that taking 2000 IU of vitamin D3 per day was associated with reduced risk of advanced (stage IV or fatal) cancer (including breast and other cancers) in those who were cancer-free at baseline. The result was strongest among normal weight individuals (BMI < 25) and did not hold for those who were overweight or obese.
- Another 2020 study found that vitamin D significantly reduced proliferation and levels of pro-angiogenetic markers in both ER+/PR+ and triple negative breast cancer cells.
- A Danish study reported that both high and low levels of vitamin D at diagnosis were associated with inferior breast cancer survival.
- A study of 1,666 women in California found that higher levels of vitamin D at diagnosis were associated with improved survival, especially among premenopausal women.
- A study reported that vitamin D supplementation in women with early stage HER2+ breast cancer was associated with improved relapse-free survival.
- A Belgian study reported that 25(OH)D levels under 30 ng/mL at diagnosis were associated with larger tumor size, but not with positive lymph nodes or tumor grade. Women with levels over 30 ng/mL had better overall survival and breast cancer-free survival than women with lower levels. In addition, levels over 30 ng/mL at diagnosis were associated with a modest favorable effect on disease-free interval (the time between diagnosis and the first recurrence, if any), which became apparent only after the first three years of follow up.
- A prospective study which used stored blood of breast cancer patients to measure Vitamin D levels found that women with deficient vitamin D levels had a significantly increased risk of distant recurrence and death compared with those with sufficient levels. The authors concluded that vitamin D deficiency may be associated with poor outcomes in breast cancer.
- A German prospective study found that low levels of circulating vitamin D at diagnosis were associated with increased risk of recurrence during the first five years.
- Still another prospective study found no association between circulating levels of vitamin D and risk of recurrence among breast cancer survivors overall. However, the same study found that dietary vitamin D intake was protective against recurrence among premenopausal women.
- A study using a mouse model found that vitamin D deficiency increased the growth of bone metastases. The study examined the intraskeletal growth of the human breast cancer cells in nude mice. Mice weaned onto a vitamin D-free diet developed vitamin D deficiency associated with secondary hyperparathyroidism and accelerated bone turnover. Osteolytic lesions appeared earlier and were significantly larger in vitamin D-deficient mice than in vitamin D-sufficient mice.
How much vitamin D is optimal?
The optimal 25(OH)D level for breast cancer prevention appears to be at least 40 ng/mL (40 to 45 ng/mL may be an appropriate target range). The appropriate vitamin D3 level goal for women undergoing treatment for breast cancer has not been established.
Optimizing vitamin D levels is not necessarily straightforward. Given that most women get little sun exposure and that there are few food sources of vitamin D, supplementation with vitamin D3 is necessary for most. This is especially true for dark-skinned women for whom vitamin D photosynthesis is less efficient and vitamin D insufficiency is very common. Obesity appears to increase the likelihood of vitamin D deficiency.
Current recommendations of 600 to 1000 units of vitamin D3 per day may not be enough to achieve a 25(OH)D level of 40 ng/mL in a reasonable period of time. Therefore, it might may sense to take 2000 units until 25(OH)D attains this level and then continue with 1000 units per day. Some studies have used doses of as much as 50000 IU/week, a dosage that appears not to result in vitamin D toxicity (which manifests as high levels of calcium in the blood, as well as bone density and kidney problems) in the short term. However, evidence to date suggests that the adverse event threshold is approximately 4000 IU of vitamin D per day for long-term use. Doses as low as 4000 per day have been found to reduce total volumetric bone mineral density and can cause kidney stones in those with genetic susceptibility. The National Academy of Medicine has set the tolerable upper intake level at 4000 IU. In addition, one study reported that individuals with 25(OH)D levels above 100 ng/mL are at increased risk for atrial fibrillation (AFib, a type of irregular heartbeat); low vitamin D levels have also been reported to be associated with AFib.
Sources of vitamin D
In addition to exposing the skin to sunlight, the following foods and supplements are significant sources of vitamin D while also having been found to protect against breast cancer:
Vitamin D appears to act synergistically with calcium in the diet to oppose breast cancer. Adequate (but not excessive) levels of calcium are required to maximize the beneficial effects of vitamin D.
Low levels of vitamin D are associated with higher risk of breast cancer. Adequate vitamin D levels at diagnosis, as well as during and after treatment, have the potential to improve long-term survival. Mega-doses of vitamin D appear inadvisable. Please partner with your oncologist or primary care physician to have your vitamin D level tested and develop a plan to increase it, if indicated.