Vitamins and Provitamins Intake as New Insights to Prevent and/or to Treat breast Cancer: A Systemic Review

Female Breast Cancer (BC) is the most diagnosed cancer across the world. The present systematic review aimed to update the new insights of vitamins and provitamins to prevent and/or to treat BC. Vitamins and provitamins are natural products that have been implicated to prevent and to treat BC. However, it is still scarce and non-consensual as reported in the literature. A systematic literature review was conducted to identify studies through PubMed, Medline, and AMBASE up to June 27, 2021 solely on the association between vitamins (or provitamins) and BC prevention or treatment. The related grey literature also was used. The results of 127 revelant publications after exclusion of 7715 papers revealed that natural vitamins and provitamis were used to prevent or to treat BC. It has been clear evidence that vitamins and provitamins reduce the risk of BC, which acting by various mechanisms with significant inverse effect and effective use in the treatment of BC. There is no indication for publication bias found, however there was high heterogeneity among studies. Despite its limitations, our systematic review provide the most comprehensive studies updated summary evidence to date on the association betweenvitamins, provitamins and BC prevention, treatment or therapeutic issues. The natural dietary of these nutrients may be encouraged among population in order to reduce the risk of BC. Thus, we hope that our publication will help for further investigation such as a large clinical trials to confirm the findings of the present study.


Introduction
In the last decades, the World Health Organization states that cancer is the second leading cause of death worldwide among noncommunicable diseases. Worldwide, an estimated number of 19.3 million new cancer cases (18.1 million without skin cancer) occurred in 2020 [1]. The global cancer burden is expected to be around 28.4 million cases in 2040, hence as a 47% rise from 2020. Female Breast Cancer (BC) is the most common diagnosed cancer and surpassed lung cancer, with an estimated over 2.3 million new cases (11.7%) and with 6.9% deaths [1]. To date, almost more than two of every five people can be develop cancer in their lifetime. The consumption of dietary modifications are one of the most promising lifestyle changes that can adjust the risk of developing cancer from human by nearly 40% [2] and for this reason the diet-cancer linkages was studied over the past decades [3]. These studies have been showed high link with nutrients quality ingested by human. Thus, numerous studies have identified some bioactive nutrients to prevent or to reduce risk of certain types of cancers during the life [4][5][6][7][8]. This suggest that agood diet, rich in fruits and vegetables which contain bioactive nutrients, is significant in the prevention of cancer development, which is in agreement with a large number of scientific papers identifying a range of bioactive compounds to prevent cancer. Certain nutrients such as vitamins, minerals, peptides, fatty acids, phenolics, and fibres may affect DNA repair, inflammation and hormones and growth factors via regulation of gene expression as well as the association to the antioxidant properties and improvement of the immune response. Particulary, epidemiological studies have correlated diet with cancer incidence and aggressiveness in many centruries [8,9]. Among these studies, vitamins and provitamins have been associated with a protective effect on cancer incidence in relation with lifestyle [10][11][12][13][14]. Fact, vitamins are organic compounds derived from plants and animals as well, however, provitamin A for example, are only synthetized in plants suggest that they need to obtain cartenoid from their diets. Vitamins and provitamins have been implicated to prevent and to treat cancer by the mechanisms of pathways involving cell growth, death and antioxidant properties as well [15][16][17]. However, the efficiency of effect of vitamins or provitamins may differ accordinaly the stage and type of cancer as well as mechanism involving in respect with age, race and other factors as well. Therefore, individual or synergism effect of the bioactive nutrients also may be potentially important in cancer-related prevention and treatment. While, many of studies showed some conflicting and/or inconlusive findings [18][19][20][21], which may be link to the methods or vitamins sources used in the study as well as race, age, menopausal status (premenopause and post-menopause) and the number of patients considered in differents studies.
In this systematic review, we aimed to summarize the most up-to-date the relevant papers on multiple role of different vitamins and provitamins to prevent and to treat BC incidence and progression, with special attention to natural vitamins/provitamins. Hence, we would highlight the associations between vitamins/ provitamins intake and breast cancer prevention and treatment, which shows insight into the comprehensive understanding of food quality intake as well as association with BC. This study also provides the comprehensive perspective for innovation and mechanism of dietary therapy and prevention of BC patients.

Materials and Methods
A literature research was conducted by utilising Google Scholar, PubMed, Medline, Scopus databases and liberay sources by selecting the terminologies "Breast cancer, prevention and treatment of Breast cancer", "Breast cancer and vitamins/provitamins","tumor", "mammary glands","angiogenesis", "Breast cancer control" etc. We searched for meta-analysis, pooled analyses, epidemiological studies, systematic reviews, prospective cohort studies, qualitative reviews andclinical studies evaluating the association between bioactive nutrients (vitamins and provitamins) and BC up until June 27, 2021. The search was not restricted by study design, and both peer-reviewed and grey literature were included. We searched some related grey literature from American Society of Clinical Oncology (ASCO), European Society of Medical Oncology (ESMO), and American Urological Association (AUA). When a large cohort study conducted after a meta-analysis was found, it was also used. Parameters used were only vitamins or provitamins (A and D) for prevention or treatment of BC.
We excluded studies that were not written on the BC and prevention or treatment and synthetic vitamins as well. Only the papers need to do focus on the association between vitamins/provitamins and breast cancer. Duplicate publications were deleted and title and abstract were checked for revelance. We found more than Seven thousand eighty huncdred and fiftytwo (7852) papers and after removal of those (7715) not meet our criteria after abstract and full text review, only one hundred and twenty seven (127) revelants publications among them as a selective compilation of approches and methodologies for our study.

Dietary source of vitamins
This part was include in the present systematic review in order to know different sources of all vitamins or provitamins used by human in their diet. Vitamins are known as an essential compounds for the normal functioning and development of the human body. These substances are classified in two classes, fat-soluble and water-soluble and act as important antioxidant compounds. Vitamin A is a fat-soluble found naturally in animal and their products [22]. It is all-trans retinol, which is an isoprenoid side chain found in animal tissue [23]. Vitamin D (active form: 1,25-dihydroxyvitamin D) was synthetized in the skin from a cholesterol like precursor (7-dehydrocholesterol) by exposure to sunlight or can be provided from animal products [24][25][26]. There are 7 different types of vitamin D, however, only two major forms, D2 and D3 which are showed important role in human body [26,27].
Vitamin E is a fat-soluble found in a wide variety of plants such as vegetables and fruits, animal or their products, however, the main source is the plant oil [27,28]. Tocopherols and tocotrienols are the two part of vitamin E compounds which differ in their saturation state of isoprenoid side chain [28,29] which confer high antioxidant activity. However, their concentrations vary within the variety and plant specices. The vitamin C is a water-soluble nutrients found mainly in fruits, vegetables and in small quantity in animal products [30]. Vitamin C is another important antioxidant used in huaman diet. Vitamins B are common micronutrients found in vegetables, fruits or in algae and edible mushrooms [31,32]. These vitamins are also found in animal products and some of them in yeasts as well. Vitamin K is also a fat-soluble nutrient, found in plant apoptose was the one mechanism known to be induced as reported by Bernardo, et al. [44] who observed that the pro-apoptotic signaling induced by retinoic acid and dsRNA was under the control of interferon regulatory factor-3 in BC cells which may lead to the death of tumor. For instance, in retinoid-sensitive cell-lines and tumors, ATRA stimulated a viral-mimicry response involving the activation of the interferon (IFN) and antigen-presentation pathways as well as other biological processes controlling the sensitivity of tumors to immune checkpoint inhibitors [45]. Further, retinoic acid may inhibit telomerase activation through inducing histone deacetylation in estrogen receptor-negative BCcells for deaths [46]. Furthermore, retinoic acid can impair estrogen signaling in BC cells by interfering with the activation of LSD1 via protein kinase A and may inhibit aromatase activation and expression, which indicates that the estrogen supply inside BC cells is insufficient to maintain cancer cell growth [47,48]. Hence, the vitamin A suggesting as important to be used for reducing risk of BC as well as to treat BC, however further molecular investigation will be done to confirm the findings for the effective therapy.
Provitamin A: The provitamin A are mainly provided from β-carotene, α-carotene and β-cryptoxanthin, however, some carotenoids such as lutein, for example, selectively induced apoptosis in MCF-7 BC cells but not in normal human mammary cells [49]. It was reported that β-carotene (provitamin A), at the physiologically concentration of just 1 μM, can decrease the expression of Bcl-2 and PARP, and NF-kB in human BC MCF-7 cells [50] by inhibiting the genes regulation of hormone involved in proliferation of cells. Fact, β-carotene treatments can also inhibit the activation of Akt and Erk1/2, subsequently decreasing phosphorylation of Bad and downregulate superoxide dismutase-2 (Sod-2, an antioxidant enzyme), its transactivation factor Nrf-2, and Endoplasmic Reticulum (ER) stress marker X-box Binding Protein 1 (XBP-1) levels [51]. Several lines of evidence suggest that carotenoids such as lycopene, β-carotene, lutein, and astaxanthin have the ability to modulate the NF-κB pathway, in some cases by inhibiting cancer cell growth via NF-κB pathway [52][53][54].
Some studies carried out such as in a pooled analysis of eight cohort studies comprising 3055 cases of BC and 3956 control subjects, showed a statistically significant inverse association which was observed between BC and levels of plasma/serum provitamin A (α-carotene, β-carotene) and lutein + zeaxanthin, lycopene, and total carotenoids [51,55]. This inverse association was strong for some receptors such as estrogen receptor-negative (ER-) compared to ER + tumors [56]. Another systematic review and meta-analysis of eight cohorts, one clinical trial, and one pooled study, comprising 19,450 BC case, dietary intake of β-carotene was significantly associated with improved BC survival (RR of 0.70) [57]. The provitamin A can act also as antioxidant because vegetables, plant oil and in small amount in animal products [33,34].

Dietary Source of provitamin A and D
Provitamin A and D are all fat-soluble nutrients found both plants and animals or their products acting as important natural antioxidants. Provitamin A provided from carotenoids which are pigments universally synthesized by all terrestrial and aquatic photoautotrophs, including plants, algae, some nonphotosynthetic bacteria, some insects, and some fungi [35]. The structure of carotenoids is based on a C40 isoprenoid backbone that may be acyclic or modified to have one or both ends modified into rings with diverse structural modifications [3]. Lycopene, β-carotene, α-carotene, lutein, zeaxanthin, and β-cryptoxanthin are the most common carotenoids in human serum, however, only β-carotene, α-carotene and β-cryptoxanthin are the sources of provitamin A, therefore the most common precursors of vitamin A. Provitamin A refers to those carotenoid precursors that are biologically active as retinol.
Provitamin D are resulting of the synthetized of vitamin D by microalgae and wild mushrooms. These forms are ergosterol (vitamin D2) which can be found in wild mushrooms, and ultraviolet-B (UVB) exposed fungi and yeast [36], 7-dehydrocholesterol in order to synthesize vitamin D3 by UVB exposure [37]. Provitamin D3 was syntheized only in microalgae [36].

Preventionand treatment of breast cancer
Vitamin A: BC remains the most common tumor found in women and one of the three most common cancers worldwide in the last years [38,39]. Natural vitamin A, or an All-Trans Retenoic Acids (ATRA), the active metabolite of vitamin A are used to prevent and to treat BC acting by many molecular mechanisms as described in different studies. Vitamin A acts by promoting the apoptosis and inhibiting angiogenesis of human BC cells or impact as antioxidant by scavenging free radicals. In line of prevention, Kim,et al. [40] found in their study, serum vitamin A levels and their relationships with other biomarkers in Korean BC patients that the serum concentration of vitamin A was associated with a seven-fold decrease in risk of benign breast disease and a six-fold decrease in risk of BC. Their results were consistent with some researchers who reported also a high reduced risk association of BC with vitamin A or provitamin A [41,40]. While, the molecular mechanism of vitamin A against breast cancer is variable and some were described by many researchers such as Mangiarotti, et al. [42] and Wu, et al. [43], who reported that ATRA induces re-differentiation of transformed cells during the early stages of the neoplastic process and promotes the apoptosis of human BC cells by regulating the Tet Methylcytosine Dioxygenase 2-Protein Kinase C zeta (TET2-PKC) pathway. Fact, the and by many pathways molecular machanisms to be effective as anticancer. For example, Zasowska-Nowak, et al. [17] observedan effect of high-dose vitamin C in advanced-stage cancer patients and found that vitamin C is effective against BC in all stages, however this can be varied with age or race. Vitamin C can generate the cell cycle arrest, caspase-independent autophagy mediated by beclin-1 and LC3 II, apoptosis via induction of apoptosis-inducing factor, induction of oxidative DNA damage, apoptosis mediated by Bax protein signalling, release of cytochrome C from mitochondria, activation of caspase 9 and caspase 3, and cleavage of poly [ADPribose] polymerase in a ROS-dependent manner. Gan, et al. [69] reported that the vitamin C inhibits TNBC (Triple Negative Breast Cancer) metastasis by acting the expression of SYNPO2 and YAP1 and therefore vitamin C may thus have a potential role in the prevention and treatment of TNBC metastasis. Vollbracht, et al. [70] found that the administration of vitamin C with standard anti-cancer therapy in the first postoperative year of women with BC resulted in significantly enhanced performance status and reduction of complaints induced by the disease and chemo-radiotherapy. Similarly, the positive impact of high-dose vitamin C on patients' performance status was also reported by the same author in the epidemiological retrospective study with 125 women with primary non-metastasized BC, receiving a basic anti-tumor therapy with vitamin C at a dose of 7.5 g once a week for at least 4 weeks. Women who received vitamin C had a significantly better performance status during adjuvant therapy and the aftercare follow-up than those who did not receive vitamin C. Carr, et al. [71] reported two case studies demonstrating improvement in a control of pain after administration of vitamin C therapy for four weeks in women with BC. In the same way, Zeng, et al. [72] found that high-dose vitamin C inhibits cell migration and invasion of BC cell lines through suppressing epithelialmesenchymal transition. Harris, et al. [73] found in their meta-analysis that post-diagnosis vitamin C supplement use was associated with a reduced risk of mortality as well as dietary vitamin C intake was significantly associated with a reduced risk of total mortality and BC specific mortality. Furthermore, Bohlke, et al. [61] reported in a case-control study in Greece, included eight hundred and twenty women with histologically confirmed BC were compared with 1548 control women, among premenopausal women, vitamin C was inversely associated with BC risk. Recently, Zhang, et al. [74] found that high vitamin C intake is significantly associated with reduced BC incidence and mortality. Thus, it may be considered as an anticancer nutrient for BC patients.

Vitamin E:
The experimental model studies in vitro and in vivo conducted by Afam, et al. [75] had shown such as antioxidative, pro-antioxidative, anti-inflammatory, modulation of cell signaling, antiproliferation, having the ability to scavenge ROS molecules which can induce the lyse of BC line [58,59], thus reduce DNA damage in cancerous tissues in human patients. For instance, a study has shown that addition of lutein and β-carotene to ROS-inducing doxorubicin at a low dose of 0.2-3.2 μM is effective against BC cell lines MCF-7 and MDA-MB-231 without influencing the redox status (lipid peroxides (LPx), sothe ROS, and lactate dehydrogenase levels) in normal breast epithelial MCF 10A cells [60]. Bohlke, et al. [61] reported also in a case-control study in Greece, included eight hundred and twenty women with histologically confirmed BC were compared with 1548 control women, among premenopausal women, provitamin A (β-carotene) was inversely associated with BC risk. Fulan, et al. [62] indicated that both the total intake of vitamin A and retinol could reduce BC risk. In addition, Bakker, et al. [63] found in a nested casecontrol study within the european prospective that high concentration of plasma provitamin A (β-carotene and α-carotene) are associated with low BC risk of ERtumors. During their study, an investigation into Cancer and Nutrition cohort, 1502 female incident BC case was included, with an over sampling of premenopausal (n = 582) and estrogen receptor-negative (ER-) cases (n = 462). Provitamin A is one the best antioxidant compounds that had different mechanisms to inhibit proliferation of cell tumor or to induce apopotosis of BC.

Vitamin K:
The different forms of Vitamin K has been proved to have a negative effect on BC in many studies, which was shown by both in vitro and in vivo studies [35,36]. Vitamin K can act in different pathways mechanism signals which consists of the production of ROS, via the 1-electron cycling of the quinone as well as by the oxidative capacity of the cell is exceeded by the increased redox-cycling of menadione and the production of ROS, resulting in its death [64,65]. Secondly, the mechanism is linked on cell cycle arrest and apoptosis induced by modulation of transcription factors, and finally the deaths of cell lines [66]. Noto, et al. [67] found in their study that vitamin K3 (13.8 μg/ mL) produced a 50% inhibition of BC cell lines and, when combined with vitamin C (99.01 μg/mL), K3 (1.38 μg/mL) increased inhibition by 74% suggesting their synergism to inhibit. It was demonstrated also that, when both vitamin C and K3 concentrations were increased (104 μmol/L and 105 nmol/L, respectively), a high effect was observed with a 93% inhibition [67]. Also, Miyazawa, et al. [68] found that vitamin K2 induced non-apoptotic cell death along with autophagy, in triple negative BC cell lines. However, cell death phenotype induced by vitamin K2 appears to differ among the type of cancers suggesting the possibility of using vitamin K2 for the BC therapy and prevention without side effects as reported for conventional drug.
Vitamin C: Consumption of vitamin C is very important for our body and lower consumption of vitamin C might increase BC risk. Fact, vitamin C acts as antioxidants apoptosis and elimination of tumor cells especially when the reinforcement of the immune system is induced. Thus, an advantage for using vitamin E in human cancer therapy is high that lead to conclude that can be used to prevent BC and to treat as well by acting via apopotic activity as reported by Theriault, et al. [93]. Kilne, et al. [81].

Vitamin D:
The vitamin D affects the cell cycle, apoptosis, hormone receptors, angiogenesis, and hypoxia, all of which are related to the BC growth, progression and metastasis [94]. Kim,et al. [42] found that severe vitamin D deficiency was found more prevalent in BC patients of Korean women than in healthy controls. Similarly, vitamin D level was significantly lower in BC patients with estrogen receptor-negative or triplenegative subtypes than in those with other subtypes [42]. National Health and Nutrition Examination Survey Epidemiologic Follow-up Study, 1971-1975to 1992 found that vitamin D reduce the risk of BC [95]. A trend toward cases of BC in woman with intakes of vitamin D above 400 IU (10 μg)/day was found associated with an 8% reduction in the risk of BC [65]. Shin, et al. [59] found also that vitamin D intake of 500 IU or more per day was associated with a significant 28% lower risk of BC in premenopausal women. Similarly, Yin, et al. [4] found in their meta-analysis, serum vitamin D and BC risk, that in case-control studies with measurement of 25 (OH) D after diagnosis showed an inverse association which was consistent with the results of Garland, et al. [96] who found a 50% lower risk of BC associated with a serum 25 (OH) D level P52 ng/mL, compared to 613 ng/mL in their study by searching the Medline database for 1966-2006. Chen, et al. [97] found in their metaanalysis that there was a significant inverse relationship between vitamin D intake and BC risk, with an overall Relative Risk (RR) of high versus low vitamin D intake for BC of 0.91 and the highest quantile of circulating 25 (OH) D was found to be associated with a 45% decrease in BC when compared with the lowest quantile. Similar inverse association was obtained by Mohr, et al. [98] in their pooled analysis of 11 case-control studies that individuals in the highest quintile versus the lowest quintile of 25 (OH) D concentrations had a reduction in BC risk, in which serum 25 (OH) D level of 47 ng/mL was associated with a 50% lower risk of BC. Also, an inverse association was found by Stoll, et al. [99] in their systematic review of 37 studies, by Shekarriz-Foumani, et al. [100] in their systematic review who reviewed (14) studies and found that serum 25 (OH) D deficiency had been very prevalent among BC neoplasms. For BCcontrolled studies, case-control studies consistently find an inverse correlation between 25 (OH) D and BC risk [101,102]. These studies suggest that elevated serum 25 (OH) D through the sun exposure and dietary intake more than 400 IU per day vitamin D supplementation decreased BC risk and recurrence. Al-Azhri, et al. [103] concluded in their study that vitamin D3 treatment antiangiogenesis, and apoptosis induction effects of vitamin E as well. Vitamin E had first acted as a non-antioxidant, α-tocopherol had inhibited muscle proliferation activity and protein kinase C activity [4]. Jiang [76] reported that Vitamin E (α-tocopherol) was used to inhibit cancer promoting pathways, including cyclooxygenase and 6-lipoxygenase eicosanoids, NFκB and signal transducer and activator of transcription factor. The reduced activity of protein kinase B and of NF-kB was shown to mediate tocotrienol reduced mammalian cancer cell proliferation [77]. Ripon, et al. [4] found an inverse association between vitamin E and BC which was exhibited to be a major difference in serum vitamin E levels and the consumption of vitamin E in cases orcontrols. Fact, vitamin E supplementation inhibited mammal's tumor cell proliferation and induced cell death in a dose responsive manner [78][79][80]. Kline, et al. [81] reported that vitamin E forms can induce BC cells to undergo apoptosis. Malafa and Neitzel [82] found also that the vitamin E inhibits the growth of BC cells in vitro and in vivo. In additon, serum concentrations of vitamins E was significantly lower in Korean BC patients and in benign breast disease patients than in healthy controls [42]. Vitamin E is potentially used for the treatment of BC in women as a chemotherapeutic agent [78][79][80]83,84]. Morever, Abraham, et al. [85] stated that vitamin E is linked with an inverse effect on BC suggesting vitamin E can delays BC risks or use for its treatment. Also, Lajous, et al. [86] reported that high folate intake was associated with decreased BC risk which was in agreement with Hu, et al. [87] who found that severe α-tocopherol deficiency could increase BC risk.
Torun, et al. [88] found a decreased serum levels of vitamin E in BC patients compared to controls suggesting the important role vitamin E for prevention from BC. Hence, Ben-Chioma and Elekima [89] propsed that the BC patients had reduced level of vitamin E suggests the possible risk of BC. Turley, et al. [90] stated that vitamin E may be of clinical use in the treatment of aggressive human BC, particularly those that are refractory to antiestrogen therapy. Other studies give evidence of a general inhibition of cell proliferation by dl-α-tocopherol, with breast [91]. Bohlke, et al. [61] reported in a case-control study in Greece, included eight hundred and twenty women with histologically confirmed BC were compared with 1548 control women, among premenopausal women, vitamin E was inversely associated with BC risk. Recent study of Godazandeh, et al. [92] demonstrated that for the treatment, vitamin Ecould be effective in breast painrelieving and decreasing nodularity with minimal side effects in comparaison with drugs. Vitamin E may inhibit the cancer formation by acting as antioxidant (quenching of free radicals) or by direct influences on tumor cells by reducing the tumor growth by induction of differentiation as well as cell cycle inhibition of pyridoxine, cobalamin), comprises a complex network of biochemical pathways that donate methyl groups for many important biological processes [124]. Thus, many studies investigated the associations between B vitamins and BC risk, however, mainly focusedonly on folate (vitamin B9), vitamin B6 and B12 [125]. For example, in China, Shrubsole, et al. [126] found in their study evidence of a decreased risk of BC associated with high consumption of folate among women who do not regularly consume alcohol suggesting alcohol may increase the risk of BC. Similar observation was done by Xu, et al. [127], who found that higher dietary intake of vitamin B1 and B3 was associated with improved survival during the followup period. The meta-analysis of observational studies indicates also that vitamin B2 intake could decrease BC risk [128], however may vary with age. Razeghian, et al. [129] compared the levels of folic acid, B6, and B12 in the plasma of 85 people with BC were measured and compared with healthy people and found a significant inverse trend observed between folate intake and vitamin B6 intake and BC risk. Zeng, et al. [72] reported also that the folate intake decreases the risk of oestrogen receptor (ER) negative (−) and ER-/ progesterone receptor (PR)-BC, with pooled risk ratios of 0.88 [95% confidence interval (CI): 0.78-1.00] and 0.82 (95% CI: 0.68-0.97), respectively and an increment of folate intake of 100 μg per day was associated with a deceased risk of ERand ER-/PR-BC.
Similar case was reported by Ren, et al. [130] who found in their meta-analysis titled association of folate intake and plasma folate level with the risk of BC: A dose-response meta-analysis of observational studies a high folate intake correlated with a low BC risk in premenopausal women. Recently, Egnell, et al. [131] found in their study that the dietary pyridoxine intakes were inversely associated with BC risk. In this way, total thiamin intake was borderline inversely associated with BC risk, so they concluded that their prospective cohort study suggesting pyridoxine and thiamin were inversely associated with BC risk. It was also reported that high plasma vitamin B6 and riboflavin lower BC risk, especially in premenopausal women [132]. In addition, Lurie, et al. [133] found that high circulating levels of vitamin B6 are associated with a reduced risk of invasive postmenopausal BC. Zhang, et al. [134] found also that folate and vitamin B6 have the potential to be chemopreventive against BC and that ensuring adequate circulating levels of folate and vitamin B6 by consuming foods that are rich in these nutrients. Shrubsole, et al. [135] reported that high intake of folate by Chinese women was associated with decreased BC risk. Furthermore, a randomized trial of combined folic acid, vitamin B6, and vitamin B12 revealed significantly reduced BC risk among women in the treatment arm of older (> 65-years-old) [136]. Lin, et al. [137] found an evidence that high circulating concentrations of folate, vitamin B6, and vitamin B12 are associated with overall can be effective against aggressive BC. Many other researchers reported significant reduction risks as well as effective therapyof BC using vitamin D [9,94,[104][105][106][107][108][109]. Furthermore, meta-analyses of population studies demonstrate an inverse relationship between vitamin D status and BC risk [110] which is consistent with the results of Tavera-Mendoza, et al. [111] who reported a number of epidemiological studies had shown that sufficient vitamin D serum levels might be protective against BC. Moreover, severe 25 (OH) D deficiency was associated with aggressive behavior of BC [112] suggesting that low circulatory 25 (OH) D could be associated with increased risk of BC. Fact, high blood 25 (OH) D levels were significantly associated with lower BC mortality (pooled RR¼ 0.58, 95% CI: 0.40-0.85) [109], and also high vitamin D levels have been shown to be associated with increased survival in patients with BC [113], however the mechanisms for vitamin D-mediated suppression of BC-relevant gene expression appear as being complex [114].

Vitamin
D may exert antiproliferative, prodifferentiating, antiangiogenic and antimetastatic effects in BC cells, thus retards the development and growth of tumours as reported by Deeb, et al. [115] and Kulling, et al. [116]. Song, et al. [117] found in their study, vitamin D intake, blood vitamin D levels, and the risk of BC: A dose-response meta-analysis of observational studies that BC risk was inversely related to blood vitamin D levels. For Story [14], vitamin D in combination with Zinc and fatty acid (ɷ-3 PUFAs) would be ideal for treating BC. Mohr, et al. [98] reported that high serum 25 (OH) D was associated with lower mortality from BC suggest that the serum 25 (OH) D in all patients with BCcould be restored to the normal range (30-80 ng/ml). Janowsky, et al. [118] found a consistent data with a protective effect of 1,25-D for BC in white women suggesting in this a clinic-based case control study that race and age can affect significantly the results of study. Hossain, et al. [119] reported that 25 (OH) D deficiency was directly related to BC and total vitamin D and supplemental vitamin D intakes had an inverse relationship with this outcome. Shirazi, et al. [120] in their study found that women with low levels of 25OHD3, as compare to women in the middle tertile, had a high risk of breast tumours with an unfavourable prognosis. The circulating form of vitamin D may induce normal cellutar proliferation by regulating genes that control the mechanism and induce differenciation, apopotosis and inhibiting angiogenesis of cell cancer [121,122].
Vitamin B: Vitamins B (B6, B9 and B12) play important roles in nucleotide biosynthesis and biological methylation reactions, aberrancies of which have all been implicated in carcinogenesis [123] and vitamins B1 and B2 can inhibit inflammation as well. Fact, one-carbon metabolism, related B vitamins (folate, thiamine, riboflavin, niacin, pantothenic acid, risk reduction of BC suggesting one-carbon metabolism may be an important pathway that could be targeted to improve BC survival. Another experimental study suggested that vitamin B6 exerts other anticarcinogenic effects by reducing cell proliferation, nitric oxide production and angiogenesis [138], and clinical studies provide evidence that vitamin B6 play a role in protection of BC [139]. Further large sample study are greatly needed to confirm their association [140]. Our study indicated that vitamins B have an important role in preventing or treating of BC when taking by BC patient.

Limitations
There are many limitations of this study. The different analyses of the data provided by the individual studies were limited and heterogenous. The results reported were differed from one to another with an estimation of risk may be less accurate than if individual data had been available. Authors used also different methods to evaluate inverse association between vitamins and breast cancer or to treat, which can affect the comparability of different studies linked with heterogeneity among studies and publications bias is impossible to be excluded when the number studies is low. In addation, missing relevant publications is possible, even if we searched via Medline, EMBASE, PubMed, etc.

Conculsion
The current review summarizes the available literature on the role of natural products, vitamins and provitamins to prevent and to treat BC. Data literature on BC associated with different were limited however, the findings of the present study indicated that natural vitamins and provitamins were inversely associated with risk of BC and used for an effective therapy. The menopausal status, race, and age as well had effectiveness to prevent or to treat BC. These findings support some recommendations for increasing the intake of vitamins and provitamins in order to prevent BC. Some studies such as clinical trials in the future will be very importantin order to confirm the findings.

Future Study
Despite the extensive effort to understand the inverse relationship between vitamins or provitamins in breast cancer development, prevention and treatment, many issues remain unclear hence clinical trials will be needed.

Funding Source
This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sectors.

Competing Interest Statement
There are no conflict of interest for this paper.