The Role of Vitamin D and its Receptor in Breast Cancer: A Comprehensive Review of the Connection and Potential Implications

Vitamin D and its receptor have attracted significant attention due to their potential roles in various biological processes, including breast cancer. Numerous studies, conducted both in vivo and in vitro, have demonstrated that vitamin D and its analogues exert control over diverse cellular mechanisms in both healthy and breast cancer cells. As a steroid hormone, vitamin D requires binding to the vitamin D receptor (VDR), a specific nuclear receptor. The VDR, in conjunction with RXR, forms a heterodimeric complex that binds to the vitamin D response elements (VDREs) on DNA, thereby regulating the transcription of genes responsive to vitamin D. Remarkably, VDR governs the expression of more than 500 genes. Investigations have revealed that vitamin D and its analogues exert regulatory effects on various hormone receptors in breast cancer, influencing treatment response and augmenting cancer cell sensitivity to therapeutic medications. With VDR being expressed in almost all tissues, the significance of vitamin D in cancer biology has been widely acknowledged. Moreover, breast cancer cells themselves express VDR. The identification of the enzyme system responsible for producing 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in breast tissue has shed light on the impact of vitamin D on both normal breast tissue and breast cancer cells. Furthermore, evidence indicates that inadequate exposure to solar radiation increases the risk of developing cancer. Given the escalating incidence of breast cancer and the widespread prevalence of vitamin D deficiency, this review aims to comprehensively explore the intricate connection between vitamin D, its receptor, and the likelihood of breast cancer development.


Introduction Outline of Vitamin-D and VDR
Since it is produced in the skin under UV radiation, cholecalciferol, the precursor to vitamin D, must be viewed as a prohormone rather than a vitamin [1].Dietary consumption is among the additional sources.Cholecalciferol is metabolised by 25 hydroxylases in the liver to a more polar hydroxylated form, which was later identified as the main vitamin circulating in the blood as 25 hydroxyCholeCalciferol [2].Only in the kidney can 1-Alpha Hydroxylase add a second hydroxyl group to create 1,25 dihydroxycholecalciferol, or Vitamin D, that assists in intestinal calcium absorption [3].Because of its extremely long half-life and high blood concentration, 25hydroxyvitamin D is regarded as the stable precursor and marker of 1,25-(OH)2 vitamin D. The form of vitamin D that circulates in the blood is 25-hydroxyvitamin D. [4].The acceptable range of 25-OH Vitamin D is between 30-50 ng/ml.An inadequate level of 25-hydroxyvitamin D is in the range of 20 and 31 ng/mL, and a value of less than 20ng/ml is regarded as a deficit [45].The Vitamin D3 receptor (VDR), a nuclear receptor belonging to the super family of Ligand-Inducible Transcriptional Regulators, is the site of action of 1,25-dihydroxy Vitamin D. Retinoid X Receptor (RXR) then forms a complex with the active vitamin D-VDR complex.The whole Complex subsequently exerts its According to this study, vitamin D should be added to the regimen of adjuvant therapy for epithelial malignancies [9].Large-scale studies have looked at how vitamin D levels are negatively related to the risk of breast cancer in a dose -dependent manner [10].High vitamin D values are substantially linked with improved carcinoma of the breast survival, according to a meta-analysis on status vitamin D and the incidence of breast cancer or death [23].Low vitamin D concentrations are strongly associated with increased cancer risk.When compared to healthy controls, the amounts of 25hydroxyvitamin D are much lower in newly identified cancer of the breast patients, and it was also found that aggressive breast cancer variations have lower amounts of vitamin D in their bodies.When compared with the early stages of cancer of the breast, reduced serum quantities of vitamin D are seen in advanced stages.The same research additionally found that Luminal breast cancer patients had larger amounts of vitamin D than those with nonluminal types.Vitamin D levels are higher in breast cancer patients with oestrogen receptor positivity than in those with oestrogen receptor negativity.Serum vitamin D levels are considerably greater in patients with a good NPI (Nottingham Prognostic Index) prognosis than in patients with an average or poor NPI prognosis group [24].According to a recent study, Luminous cancerous breast cells are affected by vitamin D, but basal-like the breast cancer cells are unaffected in terms of autophagy and antiproliferative activity.The study found that 1,25(OH)2 vitamin D has an effect upon genes of autophagy in MCF -7 cells and that this modulation is associated with patient survival.With the advancement of breast cancer, vitamin D 1,25 (OH)2 loses its ability to promote autophagy [25].According to research on the connection amongst vitamin D status and breast cancer risk in pre-menopausal ladies observed that, women with healthy weights who have reached the brief menopausal stage are more likely to experience breast cancer protection from vitamin D. In addition, Women who consume more above five micrograms per day exhibit protective behaviour [26].A case-control research conducted at six centers revealed that nline at: le o b ila Ava -1127 -consumption of Vitamin D for more than 3.57 micrograms per day has been shown to be protective against carcinoma of the breast and the results were the same across all groups [27].In both estrogen receptors positive as well as negative breast cancer cells, the 1,25(OH)2 vitamin D3 analogue, 22oxa,1,25(OH)2 vitamin D3 demonstrated anti-proliferative and can induce cell differentiation [28].Proteins Bcl2 and P53, which control apoptosis, are expressed differently with regard to vitamin D and its analogy.They boosted P53 expression while decreasing Bcl2 expression [29].A populationcantered case-control investigation identified a negative correlation between cancer of the breast and 1,25(OH)2 vitamin D3 levels.According to the study, early-life nutritional consumption and exposure to sunlight, both lower the possibility of developing breast cancer.In individuals who are at premenopausal stage, there is no conclusive connection between vitamin-D deficiency and breast cancer.This investigation result implies that the need for vitamin D rises during adolescent age, which is also a time of breast development.[30].Vitamin D concentration in blood is inversely related to circulating tumor cells, which come up with metastatic cascade.Low Vitamin D levels could be an invasive cancer biomarker [31].MCF10CA1a and MDA-MB cells were treated in an Invitro investigation on the impact of vitamin D in breast-to-bone metastasis, and it was shown that this reduced invasiveness and that the cells lost their ability to survive in the new environment following their invasion of the basement membrane.A crucial point in the metastatic process known as the epithelial mesenchymal transition (EMT) was likewise suppressed by 1,25 (OH)2 Vitamin D3.Additionally, vitamin D enhanced E-Cadherin gene expression while decreasing N-Cadherin gene expression, which are EMT indicators [32].
A research investigation found to evaluate the prospective impacts of vitamin D, a group of 512 individuals with initial-stage of breast cancer underwent clinical, pathological, and dietary examination.They found that 24.0% of patients had enough vitamin D (>72 nmol/L), 38.5% had low levels of vitamin D (50-70 nmol/l), and 37.5% turned out to be vitamin D deficient (50 nmol/l).They indicated that women with vitamin D inadequacy experienced distant recurrences following an average follow-up of 11.6 years.From the investigation, it was determined that, a lack of vitamin D may increase a likelihood for developing breast cancer [35].Population-based research consisting of a cohort of multi-ethnic and multi-centered breast cancer patients observed whether physical exercise, hormones, food habits, and other exposures influence the prognosis and survival rate of cancer of breast and reported that most of the female members of this ethnically diverse population of breast cancer victims had inadequate levels of vitamin D in their serum.This study came to the conclusion that vitamin D insufficiency may be a danger for breast cancer survivors [36].
According to research on vitamin D levels of plasma in early and late stages of breast cancer, individuals with early breast cancer had much higher amounts of the vitamin, whereas those with metastatic breast cancer have dramatically lower levels.Invasive breast cancer in Caucasian women is included in the study.Out of 279 women, 204 had early-stage breast cancer, and the remaining 75 had the illness spread to other organs [37].a prospective cohort research investigation consisting of 1295 postmenopausal breast cancer patients identified a reverse Correlation among serum 25 (OH) vitamin D and breast cancer death and considerably a higher probability of distant recurrences Therefore, in postmenopausal individuals with breast cancer, decreased serum Vitamin D levels might be linked to reduced overall survival and diminished chance of cancer-free survival [42].The prognostic outcomes of vitamin D were measured by a retrospective analysis consisting of 310 cases of breast cancer.Serum Levels of vitamin D have been shown to have a negative correlation with to the prognosis of affected individuals with subtypes of Luminal A and Luminal B. Patients with breast cancer were found to have a higher risk of recurrences than individuals with adequate amounts of vitamin D [43].An E3N group in France served as the location for a study based on case-control and the research study examined the relationship between blood vitamin D content and the risk of breast cancer.It indicated that the concentration of vitamin D in serum is lower in cases compared to controls; 75% of the women had concentrations of vitamin D below 30 ng/mL, and 37.5 percent reported values under 20 ng/mL.[44].In a research group of Iraqi women, a retrospective-prospective investigation on the connection between vitamin D and risk of breast cancer have been identified a marginally positive relationship between blood vitamin D and risk.30 controls and the study comprised 74 cases.[45].Case-control research at a pair of hospitals in Karachi evaluated the connection between sun exposure, vitamin D supplementation, and serum (25 OH) vitamin D values and breast cancer in 411 incident early-stage breast cancer cases and 784 control subjects.According to this study, patients with blood 25(OH) vitamin D levels more than 30ng/mL had a decreased risk of developing breast cancer than those with levels less than 20ng/mL The study also found that woman

The Role of Vitamin D and its Receptor in Breast Cancer: A Comprehensive Review of the Connection and Potential Implications
Available online at: https://jazindia.com-1128 -who supplemented with vitamin D for a period of an year before the registry had substantial breast cancer prevention benefits [48].
Numerous studies reported that Plasma vitamin D levels and breast cancer rates have a negative link.Nevertheless, some research revealed a positive correlation between circulating levels of vitamin D and the risk of cancer of breast.In a long-term investigation of the connection between prenatal vitamin D status and breast cancer risk and pregnancy-related breast cancer, it was discovered that vitamin D elevated the risk of pregnancy-associated breast cancers but not the risk of breast cancer during pregnancy [33].Another randomized double-blind clinical trial on the impact of supplementation of vitamin D in women who are at an increased risk for developing breast cancer before menopause.In this experiment, Two hundred and thirty eight participants were divided into two arms at random, one of which received a 20,000 IU/week vitamin D intervention and measured the density of the breasts at twelve and twenty-four months.After12 months and 24 months, bloodbased biomarkers such Vitamin D, IGF, and IGFBP-3 were also estimated.The study found no discernible differences between the interventional and placebo groups after twelve and twenty-four months of vitamin D treatment.The levels of IGF and IGFBP-3 did not significantly change after 12 and 24 months of vitamin D administration, either.This study thus contradicted previous research that demonstrated the chance of getting breast cancer was found to be negatively correlated with vitamin D intake [34].
A Case-control research in a large population estimated serum 25(OH) Vitamin D and observed that the median value of 25 (OH) Vitamin D in serum of patients is 44.9nmol and for the controls, it is 51.5 nmol,the observations of the study found a considerably inverse link between risk of breast cancer and blood Vitamin D concentration in postmenopausal women The investigation also looked at vitamin D as a constant variable in the multivariate model and observed that the risk of breast cancer decreased significantly by 0.88 every 10nM increase in 25 OH.serum vitamin D [46].The impacts of vitaminD in the breast cancer development in pre and post-menopausal women were examined in a large prospective research with 7760 incident instances of metastatic cancer of the breast, but no significant relation among breast cancer risk and vitamin D was identified [47].

Study of cell lines in
The haematological cancer cell line's sensitivity was boosted by vitamin D treatment.MDA-MB-231 and Kasumi-1 solid tumour cell lines to NK92 cells.After therapy with vitamin D, the activity of miR-302c and miR-520c was increased, the levels of each exhibited a negative correlation with those of the ligands MICA/B and ULBP2 for NKG2D.In people aged 10 to 19 who engaged in more outdoor activities, their risk of developing breast cancer was lower (e.g., OR, 0.65; 95% CI, 0.50-0.85;P for trend = 0.0006).use of fish liver oil (OR, 0.76; 95% CI, 0.62-0.92)and increased consumption of milk (OR, 0.62; 95% CI, 0.45-0.86 for a weekly average of at least 10 glasses compared to none; P for trend = 0.0004) were also associated with a lower risk.Ages 20 to 29 had weaker evidence of correlations, while ages 45 to 54 had none.In the first and second pregnancy samples, No connection could be made between the serum 25-OHD level and the risk of breast cancer (OR=1.4,95%CI 0.6-3.4;OR=1.4,95%CI 0.7-2.8,respectively), but it was linked to a higher chance of PABC (OR=2.7,95%CI The mammary gland's ductal and lobular epithelial cells express VDR.During adolescence, pregnancy, and breastfeeding, VDR and its hormone are crucial for the development of breast tissue [16].In a study, the expression of VDR was seen in lesions that were benign, carcinoma of the ducts in situ, and advanced ductal carcinoma in addition to normal breast tissue.This study found that VDR expression is 100% in normal glands, 93.5% in benign lesions, in carcinoma in situ it is 47.3% and it is 56.2% in invasive lesions, with a statistically significant difference between normal, benign, in situ carcinoma, and invasive carcinomas [17].Recent research on the expression of VDR in the nucleus, nuclear membrane, cytoplasm, and cell membrane of cancer cells revealed a statistically significant correlation between VDR negative and a number of tumour features linked to a poor prognosis.Additionally, it was noted that mastectomies were performed on VDR-negative cancers more frequently than VDR-positive cancers.A highly significant connection was identified between nuclear VDR positivity and a reduced risk of breast cancer death in breast cancers with luminal B-like molecular subtype, according to the expression of VDR about breast cancer mortality stratified by molecular subtypes [18].Numerous tissue and cell types have shown to contain VDR, and welldifferentiated cells showed the highest levels of VDR-mRNA expression.All cell lines have a sizable amount of VDR-mRNA.The significance of VDR expression for anti-proliferative activity was demonstrated by the considerable growth inhibition of MCF-7 and T47 D cells with intermediate VDR levels compared to MDA-MB-231 cells with low levels of VDR [14].

The role of VDR in adipose tissue
In an animal study, VDR-flox mice and fabp4 cre mice were crossed to produce CVF mice with adipose-specific VDR deletion.These mice showed high growth rates, increased visceral fat mass, and a substantial rise in epithelial density and the growth of the mammary gland, all of which support the antiproliferative effect of VDR on the mammary epithelium [19].

Risk of breast cancer and VDR expression
The connection between VDR expression and the survival rates of breast cancer patients was examined in a cohort study on breast cancer patients.Based on the Immuno Reactivity Score (IRS), progression-free survival, the overall survival rate, and expression of VDR in each of the three groups, the results were dichotomized into three groups.Patients with high IRS showed significantly greater progression-free survival and overall survival as contrasted with those with positive IRS for expression of VDR.[20].By using RT-PCR, Michael Friedrich et al. examined the RNA-level VDR expression in breast cancer and discovered statistically significant protein-level VDR.When compared to normal breast tissue, carcinoma of the breast patients has higher protein levels of VDR expression.However, there is no distinction at the mRNA level between soft tissue in the breast and cancer of the breast in the face of VDR [21].Silencing vitamin D receptors is linked to greater levels of autophagy, according to a new MCF-7 cell study.
After the addition of 1,25(OH)2 vitamin D, this effect remained unchanged [25].In three separate tissues-normal breast tissue, cancerous breast tissue, and healthy tissue next to cancer tissue-Kathryn Mc Carthy et al. quantified the expression of VDR mRNA.They noticed that breast cancer tissue has a stronger increase of VDR mRNA than the breast tissue that is normal and healthy tissue next to cancerous tumour.These values' biological significance is still being researched [22].In order to determine the function of VDR in the origin of carcinoma of the breast, a population-cantered case-control investigation on a sizable group consisting of 1631 cases was conducted.The study was conducted in Caucasian and African-American survivors of breast cancer among the age cohort between 35 and 64 and investigated the connection between VDR gene variation and the probability of getting breast cancer.According to the study, postmenopausal Caucasian carriers of the Bsml bb genotype had a much greater chance of developing breast cancer.The bb genotype of Bsml did not appear to be associated in any way that was meaningful with African American women.The poly(A)genotype and breast cancer risk were also found to have no discernible association in neither the Caucasian nor the African American populations.In the study, different reactions were discovered [38].
VDR was discovered to be expressed in breast cancer in a sizable population-centered cohort study involving 1114 female patients.ImmunoReactiveScore was used to categorise VDR expression into two categories: moderate and strong expressions.The study found that, rather than affecting breast cancer survival rates, the expression of VDR was inversely connected with the features of invasive breast cancer.Additionally, The research discovered that in patients older than 50, an expression of Ki67 was inversely associated to the expression of VDR [39].According to a survey of a small number of cancers of the breast patients, The occurrence of vitamin D receptors was not correlated nline at: le o b ila Ava -1133 -with other prognostic factors including oestrogen receptors, tumour T-stage, etc.Additionally, the VDR Status hasn't shown any portable changes in survival or invasion-free survival rates [41].

Aim of the study Type of Study Results
Nair Lopes et al [17] changes in pathways of metabolism and vit.D signalling in the development of cancer of breast 172 out of 306 cases of invasive tumours were studied in a cohort.Out of 131 instances of in situ tumours, 62 (47.3%) had VDR staining.
VDR was expressed often (93.5%) in benign lesions while it was expressed less frequently (56.2%) in invasive tumours.Additionally, there was a direct correlation between VDR expression and oestrogen receptor positive in breast tumours Linnea Huss et al [18] Breast cancer patient survival is correlated with the presence of vitamin D receptors in invasive breast tumours.
Over 700 primary, invasive breast tumours from the Malmö Diet and Cancer analysis underwent immunohistochemistry staining for VDR as part of a prospective cohort analysis.
Numerous tumour characteristics linked to poor prognosis were shown to be statistically considerably correlated with VDR negative, including big tumour size (p = 0.002) and higher Nottingham grade (p 0.001).
Mathew DG et al. [19] Adipose-specific VDR deletion modifies body fat and boosts mammary epithelial density.
An animal study (mice models).
• Increased body weight as a consequence to a fatty diet was caused by adipose-specific the VDR gene deletion.The abdominal fat from mice lacking the adipose-specific VDR gene showed higher Ucp1 expression.• Adipose-specific Vdr deletion increased the ductal proliferation of the breast tissue.
Nina Ditsch et al. [19] The The median VDR mRNA expression in T samples (3.3 106; p=0.002) were substantially higher than those in AN (1.65 106; p=0.002) and NN samples.

Figure 1 :
Figure 1: Illustration of the Anti-proliferative action of Vitamin D.

Table 1 :
Research on the connection between vitamin D and breast cancer is summarised