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Nutrients 2011, 3, 962-986; doi:10.

3390/nu3110962
OPEN ACCESS

nutrients
ISSN 2072-6643 www.mdpi.com/journal/nutrients Review

Chemopreventive Activity of Vitamin E in Breast Cancer: A Focus on γ- and δ-Tocopherol
Amanda K. Smolarek 1,2 and Nanjoo Suh 1,2,3,*
1

2

3

Department of Chemical Biology, Ernest Mario School of Pharmacy, 164 Frelinghuysen Road, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; E-Mail: smoaman@eden.rutgers.edu Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA The Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA

* Author to whom correspondence should be addressed; E-Mail: nsuh@rci.rutgers.edu; Tel.: +1-732-445-3400 (ext. 226); Fax: +1-732-445-0687. Received: 29 September 2011; in revised form: 20 October 2011 / Accepted: 3 November 2011 / Published: 14 November 2011

Abstract: Vitamin E consists of eight different variants: α-, β-, γ-, and δ-tocopherols (saturated phytyl tail) and α-, β-, γ-, and δ-tocotrienols (unsaturated phytyl tail). Cancer prevention studies with vitamin E have primarily utilized the variant α-tocopherol. To no avail, a majority of these studies focused on variant α-tocopherol with inconsistent results. However, γ-tocopherol, and more recently δ-tocopherol, have shown greater ability to reduce inflammation, cell proliferation, and tumor burden. Recent results have shown that γ-enriched mixed tocopherols inhibit the development of mammary hyperplasia and tumorigenesis in animal models. In this review, we discuss the possible differences between the variant forms, molecular targets, and cancer-preventive effects of tocopherols. We recommend that a γ-enriched mixture, γ- and δ-tocopherol, but not α-tocopherol, are promising agents for breast cancer prevention and warrant further investigation. Keywords: vitamin E; tocopherols; breast cancer; estrogen receptor (ER); peroxisome proliferator activated receptor γ (PPARγ); nuclear factor (erythroid-derived 2)-like 2 (Nrf2); anti-inflammatory; cell proliferation; apoptosis; case-control studies

Nutrients 2011, 3 1. Tocopherols

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Due to its antioxidant properties, dietary intake of vitamin E, a fat-soluble vitamin, has been suggested to reduce cancer risk [1]. Vitamin E consists of eight different forms which include four tocopherols (with a saturated phytyl tail) and four tocotrienols (with an unsaturated isoprenoid side chain), designated as α, β, γ, and δ variants (Figure 1) [2]. Figure 1. Chemical structures of α-, β-, γ-, and δ-tocopherols.
CH3 HO
5 6

α-Tocopherol

CH3
8

H3C 7

O CH3

CH3 CH3

CH3

CH3

CH3

β-Tocopherol

HO CH3 O CH3 CH3 CH3 CH3 CH3

HO

γ-Tocopherol
H3 C CH3 HO O CH3 CH3 CH3

CH3 CH3

δ-Tocopherol
CH3

CH3 O CH3 CH3 CH3 CH3

α-Tocopherol is known as the “classic” vitamin E, because of its superior activity over the other tocopherols in the classic fertility restoration assay [3]. α-Tocopherol is most commonly found in wheat germ, almond, and sunflower oil [4]. However, γ-tocopherol is more prominent than α-tocopherol in the American diet and is found in vegetable oils such as soybean, corn, and cottonseed [5]. δ-Tocopherol is primarily found in soybean and castor oils, and to a lesser extent, in wheat germ oil [6]. A tocopherol mixture containing 58% γ-tocopherol, 24% δ-tocopherol, 13% α-tocopherol, and 0.5% β-tocopherol (γ-TmT) can be easily available as a by-product of refining vegetable oil [7,8]. Tocotrienols are consumed more readily in East-South Asian diets, and found primarily in palm and annatto oils [9,10]. Since tocopherols are the main components of vitamin E in the American diet, this review will focus on tocopherols. The first non antioxidant function of vitamin E determined that α-tocopherol inhibited the activity of smooth muscle proliferation and protein kinase C [11,12]. Since then, three proteins have been identified to specifically bind to tocopherols: α-tocopherol transfer protein (α-TTP), tocopherol-associated protein (TAP), and tocopherol-binding protein (TBP). α-TTP is a 30–35 kDa protein and found in the liver [13] which preferentially transfers α-tocopherol from the liver to the blood [14]. The relative affinities of α-TTP for the variants of vitamin E as determined in vitro were 100% for α-tocopherol, 38% for β-tocopherol, 9% for γ-tocopherol, 2% for δ-tocopherol,

TAP is a 46-kDa protein and has the highest levels in the liver > prostate > whole brain > spinal cord > kidney > mammary gland > stomach [16]. More specifically. higher concentrations of α-tocopherol may decrease the level of γ-tocopherol in the serum [21. and δ-tocopherol is monomethylated at the 8-postion on the chromanol ring. 7-. TAP is also a cystolic lipid-binding and transfer protein. Since α-tocopherol is preferentially transferred to the blood by α-TTP. This may lead to highly instable derivatives which may act as nitrosation catalysts for secondary amines. α-tocopherol forms an intermediate tocopheroxide analogue while γ-tocopherol may form nitric oxide (NO) or a stable nitro derivative (5-nitro-γT) [32].Nutrients 2011. and 8-positions on the chromanol ring. the major tocopherol found in human blood and tissues is α-tocopherol [3]. and prostate cancer [22–27]. Although α-tocopherol may be a better antioxidant. α-tocopherol consequently has a greater capacity than γ-tocopherol and δ-tocopherol to act as a . the nitrosating agent only has the possibility to add to the para-position on the chromanol ring of α-tocopherol. breast. The ortho-positions (positions 5 and 7) for the methyl groups on the chromanol ring enhance the antioxidant properties of tocopherols and increases the solubility in lipid substrates [33]. The antioxidant properties are mostly due to the phenolic hydrogens in the chromanol ring that are donated to lipid free radicals [36]. such as pro-oxidant and toxic nitro derivatives [34].22]. Thus. γ-tocopherol is more effective in inhibiting the activity of cyclooxygenase-2 (COX-2) [23. The structural difference in the chromanol ring may be responsible for the difference in activity of each individual tocopherol form. CYP4F2 catalyzes the initial step in the vitamin E-ω-hydroxylase pathway followed by β-oxidation. The high hydrogen donation ability by α-tocopherol may cause undesirable side effects. This may be unfavorable since γ-tocopherol has demonstrated significantly greater anti-inflammatory and anti-tumor activity than α-tocopherol in several different animal models of colon. and consequently.28–32]. which removes 2 carbons from the side chain in each cycle ending in the short chain metabolite. In the liver. vitamin E is metabolized to chromanol metabolites via the hepatic protein. cytochrome P450 4F2. 3 964 and 12% for α-tocotrienol [15]. The tocopherols with a free 5 position on the chromanol ring (γ. TBP was initially found in rat liver and heart is an approximately 15 kDa cystolic protein [17] and later in human placenta [18]. Tocopherols are recognized for their inhibition of lipid oxidation [35]. α-Tocopherol is trimethylated. Both α-tocopherol and γ-tocopherol react with nitrogen dioxide NO2.and δ-tocopherol) are expected to react with nitrogen species forming C-nitroso derivatives at this position [32]. α-tocopherol may react with nitrous acid to yield α-tocopherol quinone and nitrogen monoxide gas [33]. γ-tocopherol is dimethylated at 7. TBP is involved in intracellular transport and metabolism for α-tocopherol [19]. forming a highly unstable compound and may form toxic N-nitroso-derivatives from amines [32]. carboxyethyl hydroxychromans (CEHC) [14. In addition.28] and trapping reactive nitrogen species than α-tocopherol [23. γ-tocopherol and δ-tocopherol are more readily metabolized in the liver [14]. α-Tocopherol is trimethylated at the 5-.20]. Thus.and 8-positions. Interestingly. Similar to α-TTP. The stability of tocopherol and nitrogen species derivative depends on the structure of the chromanol ring [32]. α-tocopherol with two ortho-methyl groups is expected to be a more potent hydrogen donor than either γ-tocopherol (one ortho methyl group) and δ-tocopherol (zero ortho methyl group) [33].

while the 4-OHE2 metabolite is methylated more slowly and thus highly genotoxic [49]. Subtypes of Breast Cancer Breast cancer is one of the most common malignancies affecting women and is the second leading cause of cancer death in women [44]. Both γ. and excreted out of the body [50]. Estrogen Receptor (ER) Positive Estrogen receptor positive tumors are classified as a luminal subtype of breast cancer and are reported in 60–70% of cases [45].34]. α-Tocopherol has been the most widely studied form of vitamin E for the prevention and treatment of cancer [37–40]. 17β-Estradiol and estrone are continuously interconverted by 17β-estradiol hydroxysteroid dehydrogenase (or 17β-oxidoreductase) and are the two major endogenous estrogens. Estrogens have been implicated in breast cancer. The prognosis for luminal A is better than luminal B and typically responds more effectively to selective estrogen receptor modulators. 2.and δ-tocopherol. γ-TmT may be more practical rather than individual tocopherols for the prevention of breast cancer. Breast cancer is a heterogeneous disease that can be classified into subtypes based on immunohistochemical markers. The subtypes are: estrogen receptor (ER) positive luminal A. Although the biological effects of α-tocopherol have been investigated over many decades.43]. show promise as chemopreventive agents in animal models [7.49]. The structural difference of the individual tocopherols plays a role in the variance of antioxidant properties. For example. Another possible mechanism of action may be through the metabolism of estrogen. and basal-like [45]. however. and with transition metal ions.42. other genes that encode characteristic proteins of luminal epithelial cells of origin. The etiology and pathogenesis of breast cancer remains poorly understood. and other oxidizing agents [33. lipophilicity. γ-TmT is a mixture of tocopherols enriched with γ-tocopherol and is readily available and inexpensive. As a result. estrogen may be metabolized by CYP 1A1 to form 2-hydroxyestradiol (2-OHE2) or by CYP 1B1 to form 4-hydroxyestradiol (4-OHE2). 3 965 prooxidant when present in high concentrations in vegetable oils. If catechol estrogens are not conjugated (mostly 4-OHE2). Luminal B subtype can be classified as ER positive or PR positive and is positive for HER2 [46]. but not α-tocopherol.Nutrients 2011. it may lead . ER positive luminal B. The carbon position of the estrogen molecules that are hydroxylated differs among various tissues in the body and each reaction is probably catalyzed by various CYP enzymes. while individual variants remain expensive to purify. Estrogen induces breast cancer through stimulation of cellular proliferation. These catechols may be methylated by a phase II enzyme. resulting in more opportunities for accumulation of genetic damages leading to carcinogenesis [47]. and express luminal cytokeratin 8/18 [45]. 2. and the ability to trap reactive nitrogen species (RNS). In addition. such as tamoxifen [45]. which may induce oxidative stress and play a key role in mammary cancer development [48.1. our current understanding of its role in inhibiting breast carcinogenesis remains incomplete [41]. Luminal tumors activate ER-responsive genes. lipid peroxides. One theory suggests that the mechanism is dependent on the activation of the ER. The 2-OHE2 metabolite is rapidly methylated by COMT. catechol o-methyltransferase (COMT). human epidermal growth factor receptor-2 positive (HER2 positive). Luminal A subtype is either ER positive or progesterone receptor (PR) positive but is negative for HER2. the mechanism of action still remains unclear.

4-OHE1.2. which is internalized and exerts its cytotoxic effects inside the cell [57]. ERBB3 (HER3). and poor differentiation [55]. The ErbB family is classified as a tyrosine kinase receptor and consists of EGFR (HER1). quinone 1 (NQO1). and the intracellular protein tyrosine kinase domain [61].Nutrients 2011. NAD(P)H dehydrogenase. Oxidative stress and/or electrophilic stress during redox cycling of catechol estrogens could contribute to nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation. both of which are electrophiles capable of covalently binding to nucleophilic groups on DNA which may form DNA-adducts [47]. Thus. Human Epidermal Growth Factor Receptor 2 (HER2) HER2 amplification and overexpression has been reported in 18–25% of human breast cancers [54]. The HER2-HER3 heterodimer is considered the most potent and active ErbB dimer [63–65]. HER2 signaling leads to oncogenic cell survival and proliferation through the MAPK pathway [66]. the α-helical transmembrane segment. In one study. and 2-OHE2 were capable of activating Nrf2. 2. Estrogen metabolites may exert DNA mutations from ROS or DNA mutations which may lead to the accumulation of genomic alterations essential for mammary tumorigenesis [47]. HER2 is unique in the fact that it already possesses an active tyrosine kinase domain and has no direct ligand while HER3 lacks an intrinsic tyrosine kinase activity and cannot form homodimers with itself [62]. 3 966 to the formation of semiquinones and subsequently quinones. HER2 positive breast cancer can be characterized as HER2 positive. HER3 can directly bind to the p85 subunit of PI3K to stimulate the PI3K-Akt pathway while EGFR and HER2 have additional activation steps by binding to the adaptor proteins GRB2 (growth factor receptor bound 2) and GAB1 (GRB2-associated binding protein 1) [67]. may be carcinogenic agents in breast epithelial cells [53]. and HSP90 inhibition which leads to proteasomal degradation [59]. tyrosine kinase inhibitors [58]. and PI3K-Akt pathway to promote cell survival. Other treatments include monoclonal antibody pertuzumab (binds to domain II of the HER2 receptor) [56]. The 28 women with breast carcinoma expressed 4-OHE2 levels that were 3. and ERBB4 (HER4). and cell cycle control [66]. . negative for ER. suppression of apoptosis. ERBB2 (HER2). The prognosis for HER2 positive is worse than luminal breast cancer. mainly 4-OHE2. Under normal conditions. 4-OHE2. reactive oxygen species (ROS) or RNS are neutralized by detoxifying and antioxidant enzymes [43]. HER2 positive breast cancer may be treated with monoclonal antibodies such as trastuzumab (binds to domain IV on the HER2 receptor). HER2 is a member of the epidermal growth factor (ErbB) family of transmembrane receptors which are potent mediators of normal cell growth and development [60]. the HER2-HER3 dimer leads to the MAPK pathway to stimulate angiogenesis. trastuzumab antibody conjugated with mertansine (DM1). 49 women without breast cancer were observed with larger amounts of 2-OHE2 than 4-OHE2 [53]. The structure consists of an extracellular domain at which the ligand binding occurs. ErbB receptors normally exist as inactive monomers until a ligand initiates a conformational change to induce dimerization with another receptor. while estradiol did not [52]. This suggests that a catechol structure is required for activation of Nrf2.5 times more abundant than 2-OHE2 [53]. catalyzes the reduction of quinones back to catechol estrogens [51]. however. there are HER2 positive tumors that are resistant to trastuzumab treatment [55]. proliferation. The protective phase II enzyme. This supports the finding that estrogen and its metabolites. The estrogen metabolites.

Chemoprevention is an approach to prevent cancer before a series of genetic and epigenetic events establish which otherwise could lead to malignancies. In mammary tumors.1. Cellular Events and Molecular Targets in Breast Cancer Each subtype of breast cancer responds differently to current treatments and therapy. The prognosis of basal-like tumors is poor. with frequent mutations in TP53 [69]. Administration of γ-TmT reduced ERα mRNA and protein levels in hyperplastic mammary tissues in estrogen-treated ACI rats. 3. dietary γ-TmT decreased circulating levels of E2 in the serum. there is limited in vitro. Thus.72] and can be summarized as follows: (a) inhibition of ER (b) increasing peroxisome proliferator activated receptor γ (PPARγ) expression and activity. 3 2. prevention of breast cancer is essential. The mechanisms of anti-cancer activity of tocopherols have been investigated for many years [39. high expression of basal stratified epithelial cytokeratins 5. Vitamin E has been shown to inhibit ER-positive cell proliferation and work as antagonists of estrogen signaling in MCF-7 and T47D breast cancer cells [73]. and 17.3. The incidence of basal-like breast cancer may be increased by both race and age. and the dimerization of ERβ with ERα silences the growth-promoting effects of ERα [74.75]. Basal-Like 967 Basal-like subtype is characterized by ER and HER2 negativity. in vivo. and the success of prevention strategies depends on understanding the molecular mechanism of breast cancer initiation and progression. There are two known ER receptors: ERα and ERβ. ERα and ERβ are both present in breast tissue. (c) induction of Nrf2.72. when bound to estrogen. MCF-7 cells were treated with γ-TmT.73]. The role of ERβ in breast tumorigenesis is not well understood. but the ratio of ERα to ERβ is increased in breast tumors [74]. Some studies have shown that activation of ERβ in breast cancer cell lines inhibits cell growth. induces a conformational change that allows dimerization and binding to estrogen response element sequences. 3. In addition. and (e) induction of apoptosis [28.68].70]. microarray analysis revealed that younger patients of any ethnicity tend to form basal-like tumors over other types [69. Estrogen Receptor (ER) ER is a nuclear receptor that stimulates cell growth and proliferation [48].71. Furthermore. To date. and the expression of ERα was down-regulated [7].Nutrients 2011. and human data which connect individual tocopherols for prevention or treatment for each subtype of breast cancer.43. and expression of proliferation-related genes [45. The DNA binding domain of the two different receptors is highly homologous while the ligand binding domain is 60% homologous [74]. 6. while mRNA levels of ERβ were increased [76]. (d) antioxidative and anti-inflammatory activities.69]. BRCA1 mutations are also generally basal-like breast tumors [68. The ER is a ligand-activated transcription factor that. where premenopausal African American women developed basal-like tumors (39%) compared to postmenopausal African American women (14%) and non-African American women (16%) [70]. ERα mRNA and protein levels were down-regulated by the treatment of γ-TmT [7].39. suggesting that γ-TmT may modify the response to estrogen [76]. .

tocopherols may indirectly activate PPARγ. and δ) which are ligand-regulated transcription factors [77]. Thus. Comparable to the finding in the N-methyl-N-nitrosourea (NMU)-induced breast cancer model in Sprague-Dawley rats [7]. γ. γ-tocopherol. Nuclear Factor (Erythroid-Derived 2)-Like 2 (Nrf2) Nrf2 is a transcription factor that is a key regulator of cellular antioxidant and detoxification enzymes [84]. PI3K/Akt pathway. 3 3. and more strongly δ-tocopherol enhance the transactivation of PPARγ [7]. inhibit cell cycle progression and induce apoptosis to prevent breast cancer. γ-TmT. A known PPARγ ligand is troglitazone [27]. Tocopherols. δ-Tocopherol γ-TmT γ-TmT Cell type/Cancer model Colon cancer cells (SW 480) Keratinocytes cells (NCTC 2544) Breast cancer cells (MCF-7 and T47D) NMU-induced mammary tumors in female Sprague-Dawley rats Estrogen-induced mammary hyperplasia in female ACI rats Result ↑ PPARγ mRNA and protein level ↑ PPARγ mRNA levels ↑ PPARγ transactivation ↑ PPARγ mRNA and protein level ↑ PPARγ mRNA and protein level References [27] [82] [7] [7] [76] 3.Nutrients 2011. differentiation and apoptosis markers in cancers [79]. PPARγ signaling is connected to the inhibition of inflammatory markers (COX-2. PPARγ was increased at both the protein and mRNA level in the mammary gland of ACI rats when treated with γ-TmT while ERα expression was decreased [76]. increased mRNA and protein levels of PPARγ in colon cancer cells [27] and transcriptional activity in keratinocytes cell line [82] (Table 1). Tocopherol γ-Tocopherol γ-Tocopherol γ-TmT. In MCF-7 and T47D breast cancer cells. but it was shown that γ-tocopherol does not directly bind to PPARγ [81]. the inhibition of ERα expression by tocopherols may result in the activation of PPARγ. Tocopherols induce PPARγ levels.3. and NF-κB signaling cascades [80. When ligand-activated. PPARγ forms a heterodimer with the retinoid X receptor [78]. interferes with estrogen receptor signaling.2. with γ-tocopherol displaying the strongest activity. PPAR comprises of 3 subtypes (α.81]. Recently it was thought that tocopherols might function as a PPARγ ligand because of this structural resemblance. Peroxisome Proliferator Activated Receptor γ (PPARγ) 968 Belonging to the nuclear hormone receptor superfamily. and angiogenesis while inducing CDK inhibitors. Initially. and the chromanol ring of tocopherol is structurally similar. cytokines. stimulation of PPARγ increases the degradation of cell cycle genes (Cyclin D1). Table 1. an endogenous PPARγ ligand [81]. Nrf2 activity is inhibited when bound to kelch-like-ECH-associated protein 1 . γ-tocopherol induces the formation of 15-S-hydroxyeicosatetraenoic acid.79]. and inducible nitric oxide synthase). Since PPARγ transactivation can be suppressed by ERα binding to the PPAR response element [83]. PPARγ is known to be involved in fatty acid uptake and transport and acts to control inflammation by inducing apoptosis and inhibiting cell proliferation cell survival [78. and possibly through this pathway may interfere with ERα expression. Particularly in breast cancer. γ-Tocopherol. Instead.

Apoptotic bodies are formed and the tightly packed organelles leave the cell through “budding” [96]. and −7). The mRNA expressions of phase II detoxifying enzymes were induced in the mammary gland and liver by γ-TmT treatment.95]. effectors (−3. colon. KEAP1 undergoes covalent modification which allows the release and the consequential activation of Nrf2 [84–86]. and SOD) [90] (Table 2).84–87]. Cell Proliferation and Apoptosis Apoptosis is defined as programmed cell death with distinct morphological and biochemical changes [93. Under oxidative stress or chemopreventive agents. and inflammatory (−1. In human retinal pigment epithelial cells. In breast. Our in vitro data showed that treatment with γ-TmT. and −5) [98. and treatment with γ-TmT upregulated the expression of Nrf2 and detoxifying enzymes. increased Nrf2 expression. UDP-glucuronosyltransferases. Tocopherol α-Tocopherol γ-TmT γ-TmT Cell type/Cancer model Human retinal pigment epithelial cells (ARPE-19) Prostate carcinogenesis in TRAMP male mice Estrogen-induced mammary hyperplasia in female ACI rats Result ↑ Nrf2 protein levels. and. −4. Tocopherols induce Nrf2 and related antioxidant enzymes. while the cellular membrane remains intact [94. and prostate cancer cell lines. There are ten major caspases with three main sub groups: initiators (−2. and −10).4.100]. NQO1. induced phase II enzymes (glutamate cysteine ligase. these detoxifying and antioxidant enzymes protect cells from neoplastic transformation by maintaining oxidative stress homeostasis [43. ↑ GSTm1.25. catalase.99]. the protein expression level of Nrf2 was increased in the mammary gland and liver. 3 969 (KEAP1) in the cytoplasm and is marked for degradation through the proteasomal pathway [84]. As a result. ↑ glutamate cysteine ligase. A loss of Nrf2 may lead to a decrease in cellular defense against oxidative stress which may result in tumorigenesis [89]. pretreatment with α-tocopherol inhibited ROS generation. There are two distinct apoptotic pathways: extrinsic and intrinsic [97]. −9. GST. −8. glutathione peroxidase. and NQO1) [43.Nutrients 2011. Nrf2 translocates into the nucleus.88].91]. We recently demonstrated that when estrogen-treated ACI rats were administered γ-TmT diet. catalase. HO-1. As a result. HO-1. superoxide dismutase[SOD]. and phase II enzymes were increased in the liver [92]. Table 2. and heme oxygenase-1[HO-1]). lung. NQO1. dimerizes with small Maf proteins. SOD ↑ Nrf2 protein levels.26. GST. HO-1. and phase II detoxification enzymes (glutathione s-transferases[GST]. the apoptotic cell shrinks in volume and the nuclear DNA condenses. γ-.94]. and δ-tocopherol inhibited cell proliferation in MCF-7 breast cancer cells in a . γ-tocopherol was shown to be more effective at inhibiting cell growth than α-tocopherol [7. Caspases have proteolytic activity and are able to cleave proteins. glutathione peroxidase. −6. SOD. ↑ Nrf2 protein levels References [90] [43] [92] 3. This may indicate that γ-TmT induces the transcription of Nrf2-ARE-target genes and exhibits protective defense against estrogen induced oxidative stress. and inhibited tumor development in TRAMP mice [43. and binds to the antioxidant-responsive element (ARE) to stimulate gene expression of antioxidant enzymes (thioredoxin. During the earlier stages. UGT1A1. sulfotransferases. The expression of Nrf2 was suppressed in prostate tumors [91].

Yu et al. Proliferating cell nuclear antigen (PCNA) was decreased in mammary hyperplasia [76] and in mammary tumors when administered γ-TmT [104]. In addition. Administration of γ-TmT increased the levels of cleaved-caspase 3 increased in mammary hyperplasia [76] and in mammary tumors [7]. HCT-15. Furthermore. γ-TmT γ-TmT Cell type/Cancer model Prostate cancer cells (LNCaP and PC-3) and lung cancer cells (A549) Prostate cancer cells (LNCaP) Colon cancer cells (SW480. and TUNEL assay determined that there was an increase in apoptotic cells [22].100–103] (Table 3).Nutrients 2011. whereas α-tocopherol was not active [39]. γ-tocopherol. ↑ Apoptosis ↑ Apoptosis ↓ Proliferation. ↑ Apoptosis ↓ Proliferation. δ-Tocopherol γ-TmT γ-TmT γ-Tocopherol. induced cleaved-caspase 8 and 9 in MDA-MB-435 human breast cancer cells [103]. 3 970 dose-dependent manner. when treated with γ-tocopherol. ↑ Apoptosis ↑ Apoptosis ↑ Apoptosis ↓ Proliferation ↑ Apoptosis ↑ Apoptosis ↓ Proliferation. while α-tocopherol did not [42]. colon. were shown to inhibit tumor growth more strongly than α-tocopherol in a lung xenograft model.and δ-tocopherol showed potential to inhibit colony formation. ↑ Apoptosis [100] [101] [102] [103] [22] [42] [104] [7] [105] [76] In vivo models showed that mammary tumor growth and burden was decreased by γ-TmT diet [7. Tocopherol γ-Tocopherol γ-Tocopherol and combination of γ-Tocopherol and δ-Tocopherol γ-Tocopherol γ-Tocopherol δ-Tocopherol γ-Tocopherol γ-Tocopherol γ-Tocopherol. Furthermore. δ-Tocopherol. and prostate cancer cells [26. while α-tocopherol did not [7]. showed that apoptosis was induced by δ-tocopherol in MCF-7 and MDA-MB-435 breast cancer cells [102]. tumor growth was inhibited. HCT-116. Tocopherols inhibit cell proliferation and induce apoptosis. but not α-tocopherol. HT-29) Prostate cancer cells (LNCaP) Breast cancer cells (MCF-7 and MDA-MB-435) Breast cancer cells (MCF-7 and MDA-MB-435) and murine 66cl-4 Bresat cancer MDA-MB-231 xenograft in nu/nu mice Lung cancer H1299 xenograft in nu/nu mice NMU-induced mammary tumors in female Sprague-Dawley rats NMU-induced mammary tumors in female Sprague-Dawley rats NMU-induced mammary tumors in female Sprague-Dawley rats Estrogen-induced mammary hyperplasia in female ACI rats Result ↓ Proliferation References [101] ↑ Apoptosis [101] ↓ Proliferation. γ-Tocopherol has been shown to induce apoptosis in breast. γ-Tocopherol and to a greater extent. a colony growth inhibition assay utilizing MDA-MB-435 breast cancer cells showed that γ.104]. Table 3. δ-tocopherol. . In one xenograft model.

and γ-tocopherol is more effective in inhibiting the activity of COX-2 and trapping reactive nitrogen species than α-tocopherol (Table 4) [23. In our study. In addition. Around 40% of aggressive human breast cancers are associated with high levels of COX-2 which correlates with large tumor sizes. a marker of oxidative stress. Case-Control and Cohort Studies There are several case-control. such as HER2 [107. Numerous case-control studies utilized vitamin E and . In inflamed and neoplastic tissues. 3. Studies on Tocopherols and Human Cancers 4. tocopherols may induce DNA damage leading to apoptosis. Table 4. and responsive to several oncogenes. serum levels of PGE2 and 8-isoprostane. high proliferation rates. especially α-tocopherol.1. Celecoxib. ↓ peroxynitrite ↓ COX-2 ↓ COX-2. and metastases [108]. 3 971 γ-TmT and individual tocopherols were administered to Sprague-Dawley rats which were induced with NMU carcinogen.Nutrients 2011. Tocopherol γ-Tocopherol γ-Tocopherol γ-Tocopherol γ-Tocopherol γ-Tocopherol.7) and human epithelial cells (A549) Zymosan-induced acute peritonitis in male Fischer 344 rats Human plasma Human epithelial cells (A549) Estrogen-induced mammary hyperplasia in female ACI rats Result ↓ RNS. ↓ 8-isoprostane References [29] [28] [30] [31] [111] [76] 4. Tocopherols are known antioxidants and anti-inflammatory agents. and COX-2 levels decreased in the mammary gland when treated with dietary γ-TmT [76]. γ-.5. ↓ PGE2.110]. treatment with γ-TmT. was fed to HER2/neu transgenic mice and found that there was a 50% reduction in mammary prostaglandin E2 (PGE2) levels and delayed tumor onset [109]. and the inhibitory effect was due to the decrease of COX-2 activity [28. to act as a pro-oxidant to create ROS or RNS. γ-tocopherol was shown to reduce PGE2 synthesis in macrophages and human epithelial cells [28]. Tocopherols decrease COX-2 and RNS. ↓ LTB4. ↓ TNF-α ↓ COX-2. an increase in prostaglandin synthesis is detected [107].111]. Cyclooxygenase-2 (COX-2) and Anti-Inflammatory Activities COX-2 is an inducible prostaglandin synthase which is upregulated by growth factors.28–31.108]. and intervention studies on vitamin E and human cancers. and δ-tocopherol decreased PCNA levels while increased the levels of cleaved-caspase 3 in mammary tumors. cohort. a COX-2 inhibitor. At high doses. δ-Tocopherol γ-TmT Cell type/Cancer model Carrageenan-induced inflammation in Wistar male rats Macrophages (RAW264. and cytokines [106]. tumor promoters. ↓ PGE2. were reduced when estrogen-induced ACI rats were treated with γ-TmT. whereas α-tocopherol was not active [105]. γ-TmT treatment may reduce inflammation in an estrogen-induced model of mammary hyperplasia and tumorigenesis. ↓ PGE2 ↓ RNS ↓ RNS. There is the possibility of tocopherols. but our main focus will address breast cancer.

71–1.6 IU/day Post-M: 550/1041 Post-M: 0. To date.65 mg/dL 0.46 (0.32 mg/dL.30) Serum α-T: Serum α-T: 0.67 (0.15–0.5 ~ ≥35 μmol/L 0.70 (1989 Study) 0.75) 27/28 Serum γ-T: Serum γ-T: ≤2.573 μmol/L 0.9–1. (1974 Study) 0.76 (0. 12 cohort studies did not find any relation between vitamin E and prevention of breast cancer risk (Table 6) [136–147]. they suggest that vitamin E supplement may reduce the risk of breast cancer among women who have low dietary intake [122].52–1.25–1. however.91–1.04–1.25 mg/dL γ-T: 0.73).16 (0.93) Serum α-T: 1.53–1.0) 0.50 (0.5 ~ 11.Nutrients 2011.36) Case/Control a Intake or blood levels Pre-M: 119/324 400/405 Vit E: ≤7 ~ >13 mg/day Vit E: 4.40–1.59) 223/85 levels of α-T: levels were Adipose tissue α-T: not specified 1. Case-control studies of vitamin E and breast cancer risk.79 969/969 Serum α-T or γ-T: (0.5 (0.47) Serum α-T: 0.32–0. Nechuta et al.31 (0.7 ~ 9. While investigating vitamin supplement during breast cancer treatment and survival.2 ~ ≥8. 25 μmol/L Serum α-T: Serum α-T: ≤20. (0.13–0. Table 5. In one cohort study.27 (0.94 244/244 0.85 (0.57–1.7 mg/day Post-M: 1577/1745 .46) Conclusion No association [124] Canada 1989–1993 [125] US 1976–1998 No association [126] US 1975–1994 No association [127] US 1975–1993 No association Risk reduction [113] India [129] US No association No association Risk reduction Risk reduction No association [130] [114] [115] [131] Greek Finish Uruguay Italian Pre-M: 989/841 Vit E: <8. 0.28–1.31 mg/dL α-T: 0. determined that vitamin E supplementation in the first 6 months after diagnosis may reduce risk of mortality and recurrence [148].2–1.33–1. Study Population Year Relative risk (95% CI) for highest vs.53 (0.23).26–0.40 mg/dL.73–2.10–5. lowest level Serum α-T: Serum or adipose tissue 0. but there was a weak risk reduction in post-menopausal women [145]. (0.23–0.02) Vit E: <5.34 mg/dL 0.02 30 vs.08) levels were not specified Serum γ-T: 0.62) Pre-M: 1. the European Prospective Investigation into Cancer and Nutrition (EPIC) trial observed that vitamin E did not reduce breast cancer risk.62) 115/115 Serum γ-T: Serum γ-T: 0. In the Shanghai Breast Cancer Study.12~ ≥7. 3 972 11 studies found a risk reduction [112–122].7 mg/day 0.64) 64/64 Serum γ-T: 0.4 (0.69) Serum α-T: Pre-M: 28/23 38 vs. 25 μmol/L Serum α-T: P < 0.78) Post-M: 1.93) Pre-M: 270/505 Pre-M: 0.45–1. 13 studies did not find an association with breast cancer incidence (Table 5) [123–135].96 (0.34 (0.80 (0.85 (0.99–1.05 Post-M: 29/19 Serum γ-T: Serum γ-T: p < 0.92–1.

9) 2.0) Post-M: 0.8 mg/day Supplemental Vit E: 0. . performed a meta-analysis on 38 studies between vitamin E and breast cancer [151]. Recently.2 (0.61–2.Nutrients 2011. detailed assessments revealed that vitamin E (α-tocopherol) supplements did not protect against breast cancer [149. When the cohort studies were pooled with the case-control studies.71) 0.36) γ-T: 1.96–1.3–0.94–3.71 (0.6–0.34–0.88) 0.9 mg/day (mean) Vit E: 10.6–0.7 (0. and a distinction in these case-control and cohort studies need to clarify which variant of vitamin E is utilized.21) 0.3 ~ >10.2–1.35) Dietary Vit E: 1.08 (0.13 (0.8) Pre-M: 0.150].21–13. Fulan et al.89–1. 11.10 (0.2 mg/day Vit E: 9.10) Supplemental Vit E: 1.43 mg/day Vit E: 7.7 mg/day 1.26–12.08) 0.39–1. dietary vitamin E and total vitamin E both became nonsignificant [151].9–1. dietary vitamin E and total vitamin E reduced breast cancer risk by 18% and 11%.00–4.75 (0.4 mg/day (median) Vit E: 6.4–18.0) 0. a conclusion remains elusive between breast cancer and vitamin E. [132] [116] [117] [112] [118] [119] US Italy US US US Malaysia 1977–1989 105/203 Pre-M: 988/843 Post-M: 1572/1742 297/311 Pre-M without family history: 224/251 Post-M: 313/349 57/139 362/362 289/442 2569/2588 310/353 Serum α-T: ≤21.89–1.87 (0.35–0.5 (0.66 (0.10 (0.49 (0.4 mg/day γ-T: 15.5–2.58–2.73–1.44) δ-T: 1. respectively [151].9–19.3 μmol/L Vit E: levels were not specified α-T: <6 ~ ≥11 mg/day α-T: ≤6.2–0. Thus.89–1. Previously.9) 0.9) 1.30–14.03) Dietary Vit E: 0.75 (0.13 (0.0) High supplemental Vit E: 1.4 (0.55 (0. 3 Table 5. The term “vitamin E” is used loosely.03) Low supplemental Vit E: 0.8 (0.1 vs. 6.5–1.4 IU/day Vit E: 11 vs.1 mg/day Vit E: 7.00 (0.71 mg/day [133] US 1999–2004 No association [134] Denmark 1993–1997 No association No association [135] South Korea 1999–2000 a 224/250 Pre-menopausal (Pre-M) or postmenopausal (Post-M) women. For case-control studies.59 mg/day Dietary Vit E: 4.27) 973 No association Risk reduction Risk reduction Risk reduction Risk reduction Risk reduction No association Risk reduction Risk reduction No association Risk reduction [128] South Korea 2004–2006 [120] Switzerland 1993–1999 [121] [123] Italy Germany 1991–1994 1998–1999 1996–1998 and 2002–2004 [122] China 3454/3474 1498/1559 (Non-Hispanic white) 763/877 (Hispanic) 418/394 Vit E: levels not specified α-T: 108–224 mg/day β-T: 0.2 (0.6) α-T: 0.1–12.03) β-T: 1.23 mg/day Dietary Vit E: 6.12 (1.4 mg/day δ-T: 2. Cont.6 vs.6 ~ ≥31.41–1.94–78.7–1. 5.

43) Dietary Vit E: 1.69–0.01 (0.8 mg/day (median) Vit E: 10 vs.1 IU/day Supplemental Vit E: 600 vs. 5 mg/day Dietary Vit E: <3.03 (0. 3.32 (0. which did not have an effect on lung or colorectal cancer [152.90 (0.Nutrients 2011. However.25 (0.92–1.4–19.64–1.64–1.06) Supplemental Vit E: 1.17) Supplemental Vit E: 1.91–1. 0 IU/day Vit E: ~18 IU/day (median) Vit E: <4. the ATBC study found that males supplemented with α-tocopherol acetate (50 mg daily) had 32% lower prostate cancer incidence and 41% reduction in prostate cancer deaths [154].70) 0. Intervention Studies The Alpha-Tocopherol.85) 1.21) 0.9 mg/day (median) Vit E: levels were not specified Vit E: 10 vs.17 (0. alone or in .3 mg/day Vit E: 5.14) Vit E: 1. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) administered selenium (200 μg/day) and all rac-α-tocopheryl acetate (400 IU/day) and revealed that selenium or vitamin E.153].3 ~ ≥9. 4.77–1.61–1. The Physicians’ Health Study II gave supplements of 400 IU of α-tocopherol every other day or 500 mg of vitamin C daily and concluded that neither vitamin E nor C reduced the risk of prostate cancer [155].05 (0.65–1.08 0.49) 1.2–9. 5 IU/day (median) Vit E: 19. lowest level α-T: 1.9 ~ ≥24.8 vs.01 (0. 6. Study Population [136] [137] [138] [139] Netherlands [140] [141] Finland US 1986 Canada Sweden Year 1982–1987 1987–1990 Case/Control a 519/1182 1271/59036 Pre-M: 784/53938 Post-M: 650/62573 88/4697 570/21782 Intake or blood levels α-T: <3 vs. >7 mg/day Vit E: 9.02) Dietary Vit E: 0.83 (0.4 mg/day Supplemental Vit E: 0–424 mg/day Vit E: 7–59 mg/day Dietary Vit E: 6–10 mg/day 974 Relative risk (95% CI) for Conclusion highest vs.89–1.86 (0.5 mg/day Dietary Vit E: 6.77–1.14) 0.81 (0.6–1. 3 Table 6.85–1.90–1.81 (0. Beta-Carotene (ATBC) Cancer Prevention Study examined the prevention of lung and other cancers with supplementation of all-racemic-α-tocopherol acetate (50 mg/day) and β-carotene (20 mg/day) daily.92 (0.50) No association No association No association No association No association No association No association No association No association No association No association [142] US 1976–1982 1439/89494 [143] [144] [145] Canada US Europe 1980–1987 1992–2000 325/628 Post-M: 344/18586 7502/334493 [146] US 1993–1998 2879/81926 [147] US 1991–1999 a Pre-M: 714/90655 No association Pre-menopausal (Pre-M) or postmenopausal (Post-M) women.3 vs.85–2.05) 0.13 (0.02) 1.2. Cohort studies of vitamin E and breast cancer risk.11) Dietary Vit E: 1.

1414–1416. Y. Cancer Inst. S. FASEB J. and concluded that there was no overall benefit of vitamin E supplementation [37. J.L. and from the NIEHS Center Grant P30 ES005022. 3 975 combination. W.. the Trustees Research Fellowship Program at Rutgers. the term vitamin E may be vague..158].. Z.Nutrients 2011. and more recently δ-tocopherol may contribute to inhibiting tumor formation.. The State University of New Jersey. A γ-enriched mixture of tocopherol is commonly found as a by-product of corn oil and should also be explored.. which administered supplemental natural-source vitamin E (either 400 IU or 600 IU). Natl. Papas. 2003. R. Thus. .and δ-tocopherols. These previous clinical and epidemiological studies have been primarilyutilized α-tocopherol.D. and inhibiting cell proliferation while inducing apoptosis. 123. C. The status of tocopherol as a chemopreventive agent remains unclear due to inconsistent results.W. Blot. Mark. A. Traber. It has been suggested that γ-TmT. inducing Nrf2 which consequently reduces inflammation and oxidative stress. Further investigation is warranted with γ-TmT. 13. with few studies specifying which variant is utilized.I.G.. γ. W. Conflict of Interest The authors declare no conflict of interest. Results will remain inconclusive unless the specific variant is identified for each study.157. A distinction needs to be addressed to determine the efficacy of each tocopherol variant and its chemopreventive activity. but in most cases. S. did not prevent prostate cancer [156].W. while data are lacking for γ. Constantinou. 1145–1155. Yang. bioavailability.. 5. Vitamin E and cancer: An insight into the anticancer activities of vitamin E isomers and analogs. Abnet. each which differ in chemical structure. J. Acknowledgments This work was supported in part by NIH R03 CA141756. E. and not a mixture of tocopherols or other variants of tocopherols for chemoprevention [37–40]. In previous case-control and cohort studies. Only one RCT specified using the variant α-tocopherol [158].. C. Gunter.. Brigelius-Flohe. 3. and activity. Wang. Dawsey. Vitamin E: Function and metabolism. There have been 3 breast cancer randomized controlled trials (RCT). 2...S. the studies do not identify which variant of vitamin E was utilized..M. Qiao. A. M. 1999. Taylor. References 1. Prospective study of serum vitamin E levels and esophageal and gastric cancers. epidemiological evidence between vitamin E and breast cancer is limited and inconsistent [41]. C.C. Conclusion α-Tocopherol has been investigated over many years. γ-tocopherol. P. Int. Dong. Possible mechanism of actions in inhibiting breast cancer could be: inducing PPARγ expression and as a result reducing the expression of ERα. 95. There are four tocopherols and four tocotrienols that comprise vitamin E.R.and δ-tocopherol in human prevention trials.J. 739–752. Constantinou. Cancer 2008.

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