Prevention of breast cancer is one of the greatest challenges currently facing public health researchers and policymakers. Globally, a wide range of epidemiologic studies have shown an inverse relationship between sunlight or ultraviolet-B (UVB) irradiance (the main source of circulating vitamin D in humans),1-8 oral vitamin D intake,9-14 and serum 25-hydroxyvitamin D [25(OH)D] concentration (the main circulating vitamin D metabolite),15-22 with risk of breast cancer.
There is also substantial laboratory evidence that vitamin D metabolites exert several powerful anti-carcinogenic effects on breast cancer cells including: induction of apoptosis,23 inhibition of angiogenesis,23 and helping to maintain breast epithelial cells in a well-differentiated state via upregulation of the glycoprotein e-cadherin.24
In order to assess the presence of a causal, inverse relationship, between vitamin D status and breast cancer risk, this review evaluates the scientific evidence and frames it in the context of Hill’s criteria.25 In epidemiology, the seven most important criteria postulated by Hill are used to determine whether or not a causal relationship exists between a given exposure and disease.26 Briefly, the Hill criteria are as follows:
In addition to the abundant evidence from observational studies, the powerful anti-carcinogenic properties of vitamin D metabolites, especially 1,25(OH)2D, have been demonstrated in numerous laboratory studies. Studies have shown that 1,25(OH)2D helps to maintain breast epithelial cells in a well differentiated state and downregulates expression of aromatase through several mechanisms such as inhibiting production of the COX-2 enzyme.46 Expression of aromatase also is required for synthesis of estrogen and may therefore play a role in the prevention by vitamin D of estrogen receptor (ER) positive breast cancers.46
In human breast cancer cell cultures, 1,25(OH)2D has been shown to induce apoptosis and inhibit factors that stimulate cell proliferation.23 It has also been shown that 1,25(OH)2D can inhibit angiogenesis in endothelial cell cultures in response to pro-angiogenic factors such as the signal protein Vascular Endothelial Growth Factor (VEGF).47 Furthermore, COX-2 has also been shown to increase angiogenesis, so by downregulating expression of COX-2, 1,25(OH)2D further blocks angiogenesis.23,46
Several other mechanisms have been proposed for the prevention of human breast cancer through achieving vitamin D sufficiency. One of the main attributes of malignancy in breast cancer is the loss of adhesion between cells in the terminal ductal epithelium of the breast.48 This loss of adhesion can be partly attributed to the downregulation of e-cadherin that occurs in vitamin D deficiency.49 E-cadherin is a glycoprotein that serves as a sort of glue that helps to keep cells in close contact, and, as a result, in a well-differentiated state. Breast cancer prognosis is significantly worse in the total absence of e-cadherin expression due to loss of differentiation and an increase in metastatis.24
Under the vitamin D-cancer prevention hypothesis, breast cancer occurs in several distinct phases that can be explained by a theoretical model termed the Disjunction-Initiation-Natural selection-Overgrowth-Metastasis-Involution-Transition (DINOMIT) model.50 In the first phase of the DINOMIT model, vitamin D deficiency causes the expression of e-cadherin to be downregulated, resulting in loss of adhesion and a poorly differentiated state.51 This occurs even in a triple-negative, metastatic breast cancer cell line, and results from demethylation of a promoter for e-cadherin biosynthesis.52 Another study found that downregulation of e-cadherin was a necessary condition for metastatic overgrowth of breast cancer cell lines.53 Expression of e-cadherin may be highly regulated by 25(OH)D concentration.51 High levels of circulating 25(OH)D provide substrate for conversion to 1,25(OH)2D that is synthesized via hydroxylation of 25(OH)D by the 1a hydroxylase.54 Although the principal site of this synthesis is the kidney, 1a hydroxylase is produced in a wide range of tissue, including breast epithelial tissue.54 1,25(OH)2D locally synthesized in breast epithelium is free to bind with the nuclear vitamin D receptor (VDR), unmasking the portion of the DNA that codes for assembly of e-cadherin.51,52
In the second phase of the model, Initiation, DNA is modified either through uncorrected errors that occur during replication or through exposure to mutagens such as ionizing radiation or free radicals.50 These changes in the DNA, especially changes that occur in an environment in which cells are poorly differentiated, set the stage for malignancy and unchecked cell division.
The next phase is Natural Selection. In this phase, due to the operation of evolutionary forces, malignant cells with even a 1% competitive growth advantage will eventually overtake a tissue compartment.
In the Overgrowth phase, tumor cells grow outside the basement membrane of the tissue compartment in which they originated due to increasing scarcity of essential resources, such as oxygen and glucose, that are necessary for further growth and cell division.
As the tumor continues to grow, a few malignant cells will break off from the tumor mass and be transported by the lymphatic system or bloodstream where they will colonize remote tissue sites. This is known as the Metastasis phase. During the next phase, Involution, the growth of the tumor mass is temporarily halted by a seasonal rise in serum 25(OH)D concentration. This is supported by research that has demonstrated that diagnosis for breast cancer is highest in winter when population serum 25(OH)D levels are lowest.55
Under the vitamin D-cancer prevention hypothesis, this process can be stopped at almost any point in the DINOMIT model by restoring vitamin D sufficiency in the organism. Beyond the DINOMIT model, evidence from laboratory studies has demonstrated a powerful anti-cancer effect of vitamin D metabolites on three critical phases in the development of a breast tumor: differentiation, apoptosis, and angiogenesis.23 Therefore, because vitamin D exerts such a powerful effect over a broad spectrum of processes essential for the development of a breast neoplasm, the criterion for a biological plausibility is well satisfied.
There are several well established risk factors for development of breast cancer. These include alcohol consumption,56 exogenous estrogen,57 ionizing radiation58 and in postmenopausal women, obesity.58 Obesity is associated with lower risk of premenopausal breast cancer, but higher risk of postmenopausal breast cancer.59 Physical activity is another possible factor that might be related to sunlight and time spent out of doors.60-62
Studies have also demonstrated a protective effect of physical activity on risk of breast cancer.63 However, it is difficult to separate the effect of physical activity from that of serum 25(OH)D concentration. Much of the physical activity may have been performed outdoors, and epidemiological investigations of the effect of physical activity on cancer risk rarely differentiate between indoor physical activity and outdoor physical activity. Furthermore, obesity is independently associated with low serum 25(OH)D. A reduced capacity to produce 25(OH)D in obese persons has been found in previous studies.64 Interestingly, in studies performed by Bertone-Johnson et al., Crew et al. and Engel et al., serum 25(OH)D concentration was significantly, inversely associated with breast cancer risk after controlling for physical activity.15,16,19
According to a recent meta-analysis of studies on the relationship between alcohol consumption and breast cancer risk, excess risk associated with alcohol consumption was estimated to be approximately 22%.65 This leaves a large amount of excess risk unexplained. Although a possible association between red meat consumption and breast cancer incidence has been investigated, the evidence from these investigations is inconclusive.66 Yet another risk factor that was thought to modify breast cancer risk is intake of dietary fat, theoretically by modifying levels of endogenous estrogen. However, in the Women’s Health Initiative study population, there was no effect of a low fat diet on risk of breast cancer.67 While exogenous estrogen in the form of hormone replacement therapy (HRT) increases risk of breast cancer in postmenopausal women,68 use of HRT has declined substantially since 1993, when recommendations against use of HRT were widely disseminated.69 It seems unlikely that use of HRT could account for the majority of breast cancer cases that occur every year.
This should probably be considered one of the weakest of Hill’s criteria because in the face of strong epidemiologic evidence supporting a causal relationship between a disease and exposure of interest, the presence or lack of alternative hypotheses may be largely irrelevant. None of the above risk factors can unilaterally account for all the variation between individuals in breast cancer risk. Although these risk factors, when taken together, could make a substantial contribution to predicting breast cancer incidence rates at the population level, they still cannot account for all of the differences in incidence between individual women. Exposure to the main determinant of circulating 25(OH)D concentration, UVB irradiance, tends to be ubiquitous at the population level and depends chiefly on latitude, culture, and health behaviors that are shared by large groups of people. Therefore, vitamin D status may be able to account for a greater proportion of excess risk for breast cancer than factors of lower prevalence in the population.
In previous case-control studies of serum 25(OH)D concentration and breast cancer risk, up to an 80% lower estimated risk of breast cancer was observed in subjects with the highest levels of serum 25(OH)D,20 Based on data on US population serum 25(OH)D levels from the NHANES III study and risk estimates from case-control studies,42 the estimated population attributable risk of vitamin D insufficiency could be as high as 70% for breast cancer. Results from studies on serum 25(OH)D and breast cancer risk have also demonstrated a clear dose-response relationship. In a recent meta-analysis,27 data from 11 studies were used to estimate the dose-response curve.
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