Role of Phytooestrogen in the Prevention of Breast Cancer - Coursework Example

Chapter Role of lignan is BC prevention Phytoestrogens are a group of biologically active compounds with a chemical structure similar to steroidal oestrogens and are found are many edible plants. Phytoestrogens are found in the seeds, stems, roots or flowers of plants, serving as natural fungicides and acting as part of the plant's defence mechanism against micro organisms. They also are the molecular signals that emanate from the root of leguminous plants that attract specific nitrogen-fixing soil bacteria. The main classes of phytoestrogens are the isoflavones, coumestans and lignans. Lignans are natural plant compounds with estrogenic properties and are probably the most important source of phytoestrogens in western diets. They have been suggested to have anticarcinogenic potential (Boccardo et al, 2006). Plant lignans are currently being widely studied for their potential benefits for human health as their consumption has been correlated with lower risks for developing chronic diseases, such as breast cancer and coronary heart disease. However, studies of some classes of lignans, in particular the furofurans, are hampered by the lack of suitable standards to allow accurate analysis (Haajanen and Botting, 2006). Fig.1 Lignan structures (Source: Haajanen and Botting, 2005) A study investigating the association between lignan intake and breast cancer in the early 1980s included small groups of women who were classified as vegetarian, or meat-eating. Over the course of 1 year, the concentrations of lignans excreted in their urine were compared with those of breast cancer patients who had had small breast tumours removed by surgery. The women with breast-cancer had a tendency to excrete smaller concentrations of lignans than vegetarians (Lamartiniere, 2000). Isoflavonoids and lignans are diet constituents with chemo-preventive properties. They occur in certain vegetables as their glycosides from which they are released by the bacterial micro-flora in the gut. The mechanisms by which these agents interfere with the process of carcinogenesis are only poorly understood. Although many epidemiological studies have shown that a phytoestrogen-rich diet, in which isoflavones and lignans are both found, is protective against breast cancer development (Lamartiniere, 2000) the use of soy and its isoflavone GEN by postmenopausal breast cancer patients is controversial (Duncan et al, 2003). The mammalian phytoestrogens enterodiol (END) and enterolactone (ENL) are produced in the colon by the action of bacteria on the plant precursors matairesinol (MAT), secoisolariciresinol (SECO), their glycosides, and other precursors in the diet. Both END and ENL have been shown to possess weakly estrogenic and antiestrogenic activities, and it has been suggested that the high production of these antiestrogenic mammalian lignans in the gut may serve to protect against breast cancer in women and prostate cancer in men. Various in vitro experiments suggested END and ENL significantly inhibited the growth of human colon tumor cells, and the E2-induced proliferation of MCF-7 breast cancer cells was inhibited by ENL (Wang, 2002). Human Studies Till now, the evidence for a cancer-protective role of dietary nutrients, particularly those with antioxidant properties, has been based on women without any known genetic pre-disposition and it is important to identify and evaluate dietary factors which may modify the risk of cancer in BRCA carriers. Diet modification may modulate the risk of hereditary breast cancer by decreasing DNA damage (possibly linked to estrogen exposure) or by enhancing DNA repair. The prevention of hereditary breast cancer through diet is an attractive complement to current management strategies and deserves exploration (Kotsopoulos and Narod, 2005). In a recent study by Lambert et al six lignans, including the cyclolignan 3,4-dihydroxy-3,4-dimethoxy-6,7 cyclolignan, were isolated from the flowering tops of Larrea tridentata. Furthermore the flavanone, (S)-4, 5-dihydroxy-7-methoxyflavanone, was isolated for the first time from L. tridentate or any member of the family Zygophyllaceae. All of the compounds were assessed for their growth inhibitory activity against human breast cancer, human colon cancer and human melanoma cell lines. The lignans had IC50 values of 5-60 M with the linear butane-type lignans being the most potent. The relative potency of linear butane type lignans against human breast cancer appears to correlate positively with the number of -methyl groups present on the molecule (Lambert et al, 2005). Absolute configuration of taxiresinol 1, a lignan from the heartwood of Taxus wallichiana (Himalyan yew) has been determined as 8R, 8R, and 7 R with the help of chemical correlation method and X-ray crystallography. Taxiresinol 1 showed notable anticancer activity in the in vitro bioassays against colon, liver, ovarian and breast cancer cell lines (Chattopadhyay et al, 2003). Animal Studies A study was carried out (Power et al, 2006) to determine if the lignans (END and ENL) and isoflavone (GEN), alone and in combination, have beneficial effects on bone and other estrogen-sensitive tissues from our abovementioned recent study that used a postmenopausal breast cancer mouse model (Power et al, 2006) . Bone outcomes measured included bone mineral content (BMC) and BMD and biomechanical strength properties of femurs and lumbar vertebrae. Femurs and lumbar vertebrae were specifically studied to represent areas of the skeleton that vary in their composition of cortical versus trabecular bone to determine if the skeletal effects of isoflavones and lignans are site-specific. To our knowledge, this is the first study to investigate the effects of the lignans, alone or in combination with GEN, on both bone and the uterus in a postmenopausal breast cancer mouse model. Diphenolic compounds belonging to the classes of lignans and isoflavonoids have been identified in urine of man and animals, including the chimpanzee. Some of these compounds, formed by intestinal bacteria from plant lignans and phytoestrogens, have been shown in animal studies to exhibit biological activities that suggest they could function as cancer-protective compounds. A study ( Musey et al, 1995) had been conducted in adult male chimpanzee to gauge the effect of diet on urinary excretion of these compounds and the results suggest that diet profoundly influences the excretion of both animal lignans and phytoestrogens in urine. Because non-human primates are particularly resistant to mammary and genital carcinoma on estrogen treatment, the present data suggest that the very high levels of phytoestrogens and lignans as found during exposure to the regular diet may partially account for why these primates are so resistant to hormonal manipulations to induce cancer. Cell studies Estrogen plays a major role in breast cancer development and progression. Breast tissue and cell lines contain the necessary enzymes for estrogen synthesis, including aromatase and 17 hydroxysteroid dehydrogenase (17 HSD). These enzymes can influence tissue exposure to estrogen and therefore have become targets for breast cancer treatment and prevention. A study was carried out (Brooks et al, 2004) to determine whether the isoflavone genistein (GEN) and the mammalian lignans enterolactone (EL) and enterodiol (ED) would inhibit the activity of aromatase and 17 HSD type 1 in MCF-7 cancer cells, thereby decreasing the amount of estradiol (E2) produced and consequently cell proliferation. The result of the study revealed that EL, ED and GEN have the ability to alter local estrogen production in MCF-7 cells. In the case of EL and GEN, these changes led to a reduction in cell proliferation. The study suggests that the modulation of enzyme activity by these lignans and isoflavone may be one mechanism through which these compounds exert their protective effects against breast cancer. Plant-derived phenols such as the isoflavonoid genistein and the lignan enterolactone are thought to possess cancer chemopreventive properties occur in certain vegetables as their glycosides from which they are released by the bacterial microflora in the gut. However, how these agents interfere with the process of carcinogenesis is poorly understood (Mosgau et al, 1998). Schmidt et al analysed the dose dependent combinatory activity of the phytoestrogens genistein (Gen), daidzein (Dai) and coumestrol (Cou), and 17-estradiol (E2) on cell proliferation and apoptosis induction in human MCF-7 breast cancer cells. Neither additive nor antagonistic effects on proliferation could be observed, but in contrast all phytoestrogens possessed the ability to inhibit apoptosis in the presence of 17-estradiol (Schmidt et al, 2004). Case control studies A case control study was undertaken to find out the association between phyto-oestrogens intake ( as measured by urinary excretion) and the risk of breast cancer (Ingram et al, 1997). In this study, six diet-derived phenols were compared in terms of their potencies as disintegrators of signal transduction pathways important for mitogenesis on the one hand and tumour promotion on the other. The aim of this comparison was to contribute to the understanding of chemopreventive mechanisms and to help develop screening systems for the detection of novel chemopreventive substances. The study showing an inverse relation between the risk of both premenopausal and postmenopausal breast cancer and the urinary excretion of two classes of phytochemicals, lignans and isoflavonoids. Their findings help draw attention to the potential importance of biologically active non-nutrients (phytochemicals) in foods. They also strengthen the notion that, among the phytochemicals, the phytooestrogens in particular (the two dominant chemical classes being lignans and isoflavones) seem to hold promise for reducing risk of hormone-dependent cancers ( Messina et al, 1997). The case control study showed that increased excretion of some phytooestrogens is associated with a substantial reduction in breast-cancer risk. There is a substantial reduction in breast cancer risk among women with a high intake of phyto-oestrogens, particularly the isoflavonic phyto-oestrogen equol and the lignan enterolactone. These findings could be important in the prevention of breast cancer. Emerging evidence from animal studies suggests that short-term exposure to dietary isoflavones neonatally or prepubertally decreases carcinogen-induced breast cancer by increasing the proportion of differentiated cells in the mammary gland (Murrill et al, 1996). These studies support a concept derived from other epidemiological investigations that the protective effect of the Southeast Asian diet occurs early in life (Colditz et al, 1995). This may explain why the epidemiological studies cited above, which in essence focus on the adult consumption of soy, are relatively unimpressive. Chapter 2 Role of Phyto-oestrogen in the prevention of breast cancer Soybeans and soy foods are the most significant dietary sources of the isoflavone class of phytoestrogens, which includes genistein, daidzein and biochainin A (Setchel et al, 2003). Phytoestrogens have estrogenic action on bone and the cardiovascular system but have antiestrogenic action on the breast and the uterus (Brzezinski, 1999). A recently published report of 5-year randomised double-blind study on the endometrial effects of the use of soy phyto-oestrogen in postmenopausal women revealed that 154 patients receiving 150 mg isoflavones a day for 5 years, six (4%) developed endometrial hyperplasia (five simple, one complex; no endometrial hyperplasia with atypia), compared with none of 165 patients on placebo. The same group2 also reported a randomised trial of highdose phyto-oestrogens added to clomiphene citrate, to reverse the antioestrogenic effects of clomiphene on the endometrium during intrauterine insemination. The endometrium was thicker, miscarriage rates lower, and ongoing pregnancy rate higher in patients on phyto-oestrogen plus clomiphene than in those on clomiphene alone( Unfer et al, 2004). The same group also reported a randomised trial of high dose phyto-oestrogens added to clomiphene citrate, to reverse the antioestrogenic effects of clomiphene on the endometrium during intrauterine insemination. The endometrium was thicker, miscarriage rates lower, and ongoing pregnancy rate higher in patients on phyto-oestrogen plus clomiphene than in those on clomiphene alone (Unfer et al, 2004).These findings have just reaffirmed the fact that phyto-oestrogens acts as a selective oestrogen-receptor modulator (SERM). Soy phyto-oestrogens (isoflavones genistein, daidzin, and glycitin) induce endometrial stromal-cell proliferation in vitro (Kayisli et al, 2002). The incidence of breast cancer differs in various populations of the world and migrant studies indicate that the difference is largely attributable to environmental factors rather than genetics [1,2]. The plantbased diets with high contents of phytoestrogens such as lignans and isoflavonoids have been proposed to be responsible for the low breast cancer incidence in Asian women but the mechanisms are unexplored. Experimental animal studies have supported the epidemiological data and shown a chemopreventive effect of phytoestrogens on mammary, colon, and skin tumors (Dabrosin et al, 2002). Based on their chemical structure, phenolic phyto-estrogens can be classified into four main groups: isoflavonoids, flavonoids, stilbenes and lignans (Cos et al, 2003). Fig.2 Classes of psyto-oestrogens (source: Cos et al, 2003) In recent times, many researchers focus on isoflavones, which are considered widespread in the plant kingdom, as these phyto-estrogens are mainly found in "Leguminosae" (King and Young, 1999). Within this specific plant family, they are especially abundant in soybean: approximately 2g of isoflavones can be found per kilogram fresh weight (Reinli and Block, 1996). Coumestrol is a phytoestrogen found in alfalfa and animal foodstuffs and is thought to have potent oestrogenic activity. However, reported relative binding affinities have varied from Read More