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Role of Vitamin E in Prevention of Breast Cancer: An Epidemiological Review

Breast cancer rates are so high among women in more developed countries, rates are increasing in almost every region of the world. In 2018, it is reported that 627,000 women died from breast cancer. Vitamin E is a common supplement characterized by its antioxidant potential effects on many chronic conditions that prevent free radicals from harming DNA, protein and cell membranes may serve as a part of cancer growth by reducing oxidative DNA alteration. The major forms of vitamin E as an anticancer agent, which acts as major antioxidants to regulate peroxidation reactions and control free-radical production within the body, are tocopherols and tocotrienols. Since Vitamin E had first acted as a non-antioxidant, α-tocopherol has inhibited smooth muscle proliferation activity and protein kinase C activity. Although tocotrienols are mostly investigated as antioxidant effects of tocotrienol, which plays an important role in reducing the damage to DNA by decreasing the by-product of lipid peroxidation. This study aims to investigate the connection between vitamin E and also the risk of breast cancer and the outcome is that some inverse Review Article Ripon et al.; AJARR, 11(3): 37-47, 2020; Article no.AJARR.58489 38 relationship between vitamin E and breast cancer exists. There has been clear evidence that vitamin E reduces the risk of human cancer but our main focus is on breast cancer, seen in many prospective and retrospective case-control, cohort and intervention studies.


INTRODUCTION
Countries in South Asia face a secret epidemic of breast cancer [1]. Breast cancer is the most frequent cancer among women, impacting 2.1 million women each year, and also causes considerable number of cancer-related deaths among women. In 2018, it is reported that 627,000 women died from breast cancer -this is approximately 15 % of all cancer deaths among women. While breast cancer rates are so high among women in more developed countries, rates are increasing in almost every part of the world [2]. While breast cancer is primarily a postmenopausal women's disease in developed countries (less than 50years), almost half of all cases of breast cancer (45%) in developing countries were diagnosed in 2010 in reproductive women (15-49 years) [3]. We estimate that 30,000 women in cases of breast cancer will have an annual new burden in Bangladesh. In South Asia, the incidence of breast cancer in combination with increased life expectancy and population growth [4] and the adoption of "Western" lifestyles (higher fat diets, less activity, reduction in parity, delayed childbirth, and decreased breastfeeding) is expected to increase [5]. While countries with high incomes are celebrating dramatic advances in breast cancer care for women, countries with low incomes, such as Bangladesh, are just beginning to realize how severe and dangerous the disease is [4][5][6].
The leading cause of death within the world is currently breast cancer, which is the leading malignancy (neoplasm tumor) diagnosed in women, which is about 25% of all cancers, that of 15% of all deaths of cancer [7][8]. More than half of the women who have been diagnosed with breast cancer in the world do not seem to be due to known disease risk factors [9]. The risk of cancer by free radicals acting on biological systems through oxidative processes is increased by these poisonous chemicals [10].
Natural antioxidants are neutralized in free radicals, which cause tissue damage to molecules with one or more unpaired electrons [11]. Free radicals are produced through ionizing radiation in normal or pathological cell metabolism. An important characteristic of radicals and free radicals' reaction is their lead to new radicals, leading to chain reactions [12]. Despite antioxidant defense like vitamin E, damage to proteins and DNA associated with OFR accumulates through life and is claimed to lead to breast cancer [13][14][15]. There has been compelling evidence over the last few years that the rise of the incidence of cancer in an aging population can be reversed through the removal of preventable OFR sources or improved antioxidant defense systems [16][17][18]. Diet and nutrition have been seen as a successful preventive method for cancer. Substantial experimental findings suggest that several natural dietary products could affect breast cancer growth and development, such as soy, pomegranate, mangosteen, citrus fruits, apple, grape, mango, cruciferous vegetables, ginger, garlic, black cumin, edible macro-fungi, and cereals [19]. Some recommended foods, such as probiotic products and lemon have patented the benefits of anticancer. Other major illnesses such as cardiovascular disease, hypertension, hypercholesterolemia, cancer, and other possible diseases can be suppressed and treated with probiotics [20]. Accumulated evidence from studies indicates that the dietary consumption of lemon and lemon products (such as lemon peel, lemongrass oil, lemon extract) supposes to be inversely correlated with the decreased risk of various infectious diseases and cancers [21].
Of all the foundations of cancer treatment, chemotherapy is one. While the procedure increases cancer patients' survival, it causes substantial toxicity. In addition to acute toxicity such as nausea, alopecia, oral mucositis, and depression in the bone marrow, long-term side effects are going to reduce these patients' standard of life. The cross-linking of radicalmediated DNA is one of the ways in which most treatment medicines have their cytotoxic effects [22,23].
The body has several ways to combat oxidative stress by generating antioxidants, which are produced either naturally or given externally by food (exogenous). The antioxidants' role is to neutralize the excess of free radicals, protect cells from their toxic effects, and reduce oxidative DNA alteration to prevent tissue, organ damage, and primary cancer prevention [24]. Our dietary antioxidants play a key role in the neutralization of oxidative stress by endogenous antioxidants. The structure and antioxidant function of each of the nutrients is unique [25]. They will also interfere with the action of therapeutic agents acting alone through the production and induction of apoptosis by reactive oxygen species [26]. The proposal has been made to protect the breast tissues from oxidizing damage that might lead to the development of cancer by lipid-based soluble antioxidants, such as vitamin E [27]. Lipid-soluble antioxidants, such as vitamin E, have been suggested to protect the breast tissue from oxidant damage that can lead to cancer development [28]. The current evidence for a relationship between vitamin E as antioxidant and breast cancer will be examined in this review. This paper aims to examine the relation between vitamin E and the risk of breast cancer as well.

EXECUTIVE SUMMARY
The health benefits of vitamin E, including antioxidants, neuroprotective and anti-increasing properties, are well-known. A vital, fat-soluble nutrient that works as an antioxidant within the human body was found in vitamin E [29]. Tocopherol is derived mainly from vegetable oils and animal fats, which are of critical importance in body membranes and represent a group of compounds divided by two sub-groups called tocopherols and tocotrienols. They serve as important antioxidants that control peroxidation and free radical production within the body [30,31]. The eight different forms of this family of compounds are in the two categories: 4 saturated analogs (α, β, γ, and δ), known as tocopherols, and 4 unsaturated analogs known as tocotrienols [29-31].

Tocopherols as Anticancer Agents
A category of phenolic fat-soluble compounds is the tocopherols, the principal form of vitamin E (Fig. 1). Each tocopherol consists of a chromanol ring and a sixteen carbon phytyl chain. Tocopherols are called α, β, γ and δ depending on the quantity and location of the methyl teams on the chromanol ring. Alpha-tocopherol (α-T) is tri-methylated at the ring's 5-7-and-8-specific locations, and β-T is di-methylate at 5-and 8specific locations, whereas γ-T is di-methylate at 7-, 8-specific locations and δ-T is methylated at 8-specific locations [33]. The 5-and 7-position non-methylated carbons are electrophilic centers, capable of effectively trapping reactive oxygen and nitrogen (RONS). All tocopherols are strong antioxidants but α-T and α-T are more effective than α-T at trapping reactive nitrogen species and effectively mitigates lipid-free radicals by reducing single-electron. This is potentially the most important physiological antioxidant mechanism to secure biological membranes [33,34]. Vegetable oils, such as corn oils, soybeans, sesame, and nuts are the major dietary sources of tocopherols. In these oils, γ-T is 3 to 5 times higher than α-T, and δ-T is as abundant as α-T, whereas β-T exists in only minimum amounts [35,36]. However, γ-T rich mixture of tocopherols (γ-TmT) is a by-product in the distillation of vegetable oil and usually contains (per gram) 130 mg α-T, 15 mg β-T, 568 mg γ-T, and 243 mg δ-T has demonstrated for cancer prevention activities [37-39].
As a result of vitamin E's first non-antioxidant function, α-tocopherol inhibited smooth muscle growth and protein kinase c. Since then, three proteins have been specifically identified for binding tocopherols: α-tocopherol transfer protein (α-TTP), tocopherol-associated protein (TAP), and tocopherol-binding protein (TBP).α-TTP is a 30-35 k Di protein (a baculoviral protein that prevents apoptosis in virus-infected cells) located in the liver moving α-tocopherol preferentially from the liver to the blood [40-42]. Thus αtocopherol is the major tocopherol found in human blood and tissues [43]. Tocopherols are known to inhibit lipid oxidation from hydroxyl radicals as well as alkoxyl radicals, peroxyl radicals, singlet oxygen, and possibly the number of oxygen and metal complexes. These agents do not alone harm lipids. However, produce secondary intermediates, lipid hydroperoxides that start a chain reaction of lipid peroxidation, and decompose into alcohol and organic peroxyl radicals. Tocopherols protect lipids without Many studies indicate that a lower nutritional status of vitamin E is associated with a greater risk of certain cancers so that it is proposed that tocopherols reduce cancer risk [47,48]. α-T has therefore been the most commonly used form of tocopherols, which are more capable of acting as a prooxidant for cancer prevention studies than γ-tocopherol and δ-tocopherol. However, the findings of large-scale human intervention experiments using α-T such as the Alpha-Tocopherol-Beta-Carotene Cancer Prevention Experiment and the Selenium-Vitamin E Cancer Prevention Studies have led to conflicting conclusions on the cancer prevention activities of tocopherols [49].

Tocotrienols as Anticancer Agents
Tocotrienols contain a phenolic hydroxyl group on the number of 6 carbon of the chromanol ring as well as tocopherols. Classified as α, β, γ, and δ which act as the reactive site responsible for mediating antioxidant activities, depending on the number and the position of methyl groups within the chromanol ring. While tocotrienols are also potent antioxidants that interfere with peroxidation and control the body's free-radical generation (Fig. 2) [33, 34]. Breast cancer is primarily screened for cancer to determine tocotrienol anti-cancer activity [50,51]. In one trial tocotrienols showed significant in vitro anticancer activity in the normal mammalian epithelial cells against extremely malignant mammalian Cancer cells with minimum toxicity [52]. The anti-cancer activity was measured by decreased proliferation. Furthermore, the reduced activity of Akt (protein kinase B) and of NF-kB (a protein complex that controls transcription of DNA, cytokine production, and cell survival) was shown to mediate tocotrienol reduced mammalian cancer cell proliferation [53]. A recent animal study showed significant reductions in oxidant DNA damage from the consumption of tocotrienol. Oxidative stressinduced DNA damage is the primary cause of the genetic mutation in mammalian cells. The damage to unrepaired DNA builds up and may result in cancer. Tocotrienol has recently been suggested to play a protective function from oxidative stress DNA damage that could contribute to its chemo-preventive function [54]. Tocotrienol seems to have a major anti-oxidant effect since the decreased damage to DNA was associated with a decrease in lipid peroxidation by-products [55]. Initially, studies investigating the effects of high dietary intakes of fat on mammary tumorigenesis in a laboratory found that the use of fatty diets significantly stimulates the development of carcinogenic mammary tumors [56,57]. Other research studies have investigated the effects of dietary vitamin E supplementation from palm oil, commonly known as the tocotrienol-rich fraction (TRF) mixture, containing α-tocopherol (20%), α-tocotrienol (16%), γ-tocotrienol (44%), δ-tocotrienol (15%) and non-vitamin E contaminants (5%). That supplementation inhibited mammal's tumor cell proliferation and induced cell death in a doseresponsive manner [50,52,58]. Direct comparisons among the two subclasses in   [52,59]. These studies were generally the experimental evidence of tocotrienols' anti-cancer activity and suggested that such vitamin E may be potentially used for the treatment of breast cancer in women as a chemotherapeutic agent [50,52,58,59].

RESULTS
In most cases, samples and active trials concentrate on breast cancer, and human cancer No vitamin E have shown that tocotrienols are much more powerful than tocopherols for suppressing growth and inducing cell death [52,59]. Such research studies also indicate that tumor cells substantially more sensitive than normal mammalian epithelial cells to the anti-proliferative and apoptotic behavior of tocotrienols [52,59]. These studies were generally the experimental cancer activity and ch vitamin E may be potentially used for the treatment of breast cancer in women as a chemotherapeutic agent In most cases, samples and active trials concentrate on breast cancer, and human cancer research is performed. Such studies have been performed in women with vitamin E, especially in premenstrual and postmenstrual women. These hypotheses showed that there was a significant difference between α-T plasma levels and higher dietary intake of rich vitamin E food over a long time between the subsequent cancer group and the non-cancer-causing group (Table 1) [60][61][62][63][64].
Different experimental designs in retrospective and prospective case-control have commonly been used to test a hypothesis that the plasma level of α-T is inversely associated with the risk of cancer. The studies were listed in Table 2. Most future research, however, use people in both men and women who do not eat additional research is performed. Such studies have been performed in women with vitamin E, especially in premenstrual and postmenstrual women. These hypotheses showed that there was a significant T plasma levels and higher vitamin E food over a long time between the subsequent cancer-causing causing group Different experimental designs in retrospective control have commonly en used to test a hypothesis that the plasma T is inversely associated with the risk of cancer. The studies were listed in Table 2. Most future research, however, use people in both men and women who do not eat additional

DISCUSSION
Many control studies using vitamin E, four studies showed a reduction of risk of breast cancer, but one did not find a combination of the incidence of breast cancer (Table 1). In breast cancer patients, vitamin E was measured at the different clinical stage and menopausal status of 54 patients with breast cancer, 28 were premenopausal, and 26 were post-menopausal. The levels of Plasma Vitamin E had a certain association, with low levels associated with much greater cancer risk. The disparity in the mean amounts of vitamin E between the cases and controls was 3 μmol / L; and 13 μmol / L and 5 μmol / L respectively for the pre-and postmenopausal women. The total nutrient consumption of vitamin E and plasma vitamin E was in contrast to controls substantially lower in cases [60]. Differential serum vitamin E levels and higher dietary vitamin E diet rich in cases and control studies in pre-post menstrual women have been observed in these studies. The inverse association between vitamin E and breast cancer has been shown to be a major difference in serum vitamin E levels and the consumption of vitamin E rich food in cases or controls. There were considerable differences in the serum vitamin E levels in these four studies between the cases and controls. Women with the lowest α-T quintile were more likely to develop cancer [60][61][62][63]. However, one study did not establish an association with the incidence of breast cancer because it is difficult to show a reverse relationship between vitamin E and cancer, because of the lack of significant differences in vitamin E levels between case and control [64].
In humans, numerous experimental retrospective and prospective case-control designs were performed to establish the association of vitamin E with cancer (Table 2). Numerous case-control studies utilized vitamin E and four studies found a risk reduction (65)(66)(67)(68), but three studies found no association with the incidence of breast cancer [69][70][71]. The plasma levels of α-T of 39 women who eventually developed breast cancer were assessed in a prospective study of 5,004 participants, and of 78 controls who did not. The plasma levels of vitamin E showed a certain correlation, with low levels correlated with much higher cancer risk. In cases and controls the mean vitamin E levels were 4.7mg\L and 6.0mg\L. Cancer incidence was approximately five times higher for the lowest quintile's women with vitamin E compared to the highest quintile's women with vitamin E [65]. Similarly, serum α-T was measured for a similar study of 15,093 women who participated in the Finnish Social Insurance Institution's Mobile Clinic Health Survey. Among this survey study, 313 women were developed cancer and 578 controls that did not. There has been an inverse association between serum vitamin E concentration and cancer risk. Women with the lowest α-T quintile were 1.6 times more likely to have cancer than women with the highest α-T quintiles. In all cancer cases, the average amount of serum α-T was around 10 mg\L and 10.38 mg\L in the controls (66). Another prospective study with 295 men and women measuring serum vitamin E levels from 99 cases to 196 controls where vitamin E was lower in the cases than the controls (10.5±3.2 vs. 11.9±4.90 mg per liter). Due to large standard deviations, the vitamin E values between cases and controls have to overlap considerably. The risk of lung cancer was 2.5 times greater for those with the lowest quintile vitamin E levels than for those who had the highest quintile vitamin E levels [67]. Serum vitamins E and Se in 150 individuals who have developed gastrointestinal cancer and 276 controls that did not have been determined in a prospective study of 36,265 Finnish men and women. For both men and women, the mean value of α-T for cases was 7.83 mg\L and 9.87 mg\L where 8 mg\L and 10.7 mg\L were respectively for controls. The risk of cancer of the upper gastrointestinal tract was increased for subjects with low concentrations of α-T [68].
However, in the same prospective study, 5,086 people were screened between 30 cases and 288 controls for serum vitamin E. The α-T value was 6.5 mg\L and 6.2 mg\L respectively, for both cases and controls. The inverse association of serum vitamin E levels to the risk of breast cancer was not observed [69]. Another prospective study involving 321 men and women were measured with serum vitamin E levels within 111 cases and 210 controls. Serum vitamin E levels were somewhat lower in subjects who later had cancer than in controls and vitamin E levels for case and controls were 1.16 mg\dl and 1.26 mg\dl respectively where the case-control difference was 0.1 mg\dl. These findings do not support the hypothesis about antioxidant vitamin E intake or serum levels at a reduced cancer risk (70). The dietary supplement and the plasma α-T levels were assessed with α-T values for the cases of women 0.97 mg\dl and for the controls 0.969 mg\dl respectively in a retrospective case-control analysis involving 108 cancer cases and 152 controls. Measuring the plasma or serum levels at just one or two times and without any great vitamin E differences between cases and controls makes it extremely difficult to establish a definite possible connection between the plasma vitamin E level and the risks of cancer. The plasma vitamin E levels and the risk of cancer were also not inversely related. However, as discussed earlier, this retrospective experimental design is not appropriate for such a conclusion [71].

CONCLUSION
This review summarizes the studies based on epidemiology, interventions and experiments related to cancer prevention activities of tocopherols and tocotrienols as an anticancer agent of vitamin E. In addition, the antioxidant and anticancer activities of the individual members of various subgroups of Vitamin E are of a wide variety. In particular, tocotrienols are significantly more anti-proliferative and apoptotic than tocopherols in a number of experimental models of breast cancer, indicating that dietary supplementation tocotrienols can avoid or decrease the risk of breast cancer in women.
The relationship between single vitamins and the risk of breast cancer was the most significant. However, further research appears to be justified on whether vitamin E plays a role in the prevention of breast cancer. Vitamin E serum levels are likely preferable to dietary recall because they reflect long-term exposure. Tissue oxidant damage measurements and α-tocopherol levels could be even more informative as this site reflects the intake and use of action. A pilot study is being undertaken to determine if α-tocopherol and oxidative damage in the breast tissue levels can be measured and utilized as risk markers for breast cancer. In summary, breast cancer is a serious universe problem, and progress in preventing breast cancer would be very useful in significantly reducing the burden of breast cancer risk and death among women. Dietary antioxidant supplementation, particularly vitamin E, is associated with cellular dysfunction and death to protect against free-radical damage.
Although dietary changes are not easy in an attractive breast cancer prevention procedure. As the animal evidence is promising, there have been limited but promising evidence from human studies, and vitamin E is so safe, additional vitamin E and breast cancer risk associations are predicted.