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Phytoestrogens and breast cancer: friends or foes?

Phytoestrogens

Phytoestrogens, which are widely distributed in plants, are structurally similar to mammalian estrogens and can thus bind weakly to estrogen receptors. The three major classes of phytoestrogens are the isoflavones, lignans and coumestans. The best known phytoestrogens derived from the diet are genistein, daidzein and glycitein which are the isoflavones found in soy beans, particularly in ferments of soy. They almost exclusively occur as glycosidic conjugates and in unconjugated or conjugated forms in most soy protein products in high concentrations. Smaller amounts have been found in other beans and in some vegetables and fruits (Kurzer 1997).

The interest in phytoestrogens derives from the observation that hormonally dependent cancers are not highly prevalent in Asian countries and amongst vegetarians when compared with data collected in Western populations (Adlercreutz 1999). These diets have consistently shown low plasma concentrations of insulin and IGF1, two potent mitogens, and high concentrations of IGF1 binding proteins (IGFBP). This combination of low IGF1 and high IGFBP is known to reduce breast cancer risk in premenopausal women (Giovannucci 1999). These findings have suggested that phytoestrogens may have a preventive effect against various cancers.

The three most estrogenic phytoestrogens are genistein, coumestrol (a coumestan) and equol. These phytochemicals belong to a larger class of polyphenols characterised by non-steroidal structures similar to mammalian estrogens, such as estradiol, and have estrogenic properties. Given their low molecular weight and stable structure, phytoestrogens are able to interact with estrogenic enzymes and receptors (Adlercreutz 2003). This interaction allows phytoestrogens to bind and alter the structure of estrogen receptors and alter transcription (Santii 1998). Most of all phytoestrogens inhibit the enzyme needed for hormone conversion, which may reduce cancer by lowering the biological activity of sex hormones in specific tissues (Adlercreutz 2003). Evidence that phytoestrogens can mimic endogenous estrogens has raised concerns about their effects on cell growth and proliferation (Bath 2002).

To resolve the dilemma regarding the potential benefits or harmful effects of phytoestrogens in breast cancer development, numerous studies have attempted to characterise the estrogenic and growth stimulatory actions of phytoestrogens. Most of these studies have been carried out in breast cancer cell breast lines and the result of these studies points to the unique quality of phytoestrogens to bind to estrogen receptors ER-alpha and ER-beta and modulate the activity of ER signalling cascades and transcription factors, thereby exerting an inhibitory effect on cell proliferation and survival. Many phytoestrogens display a somewhat higher affinity for ER-[beta] compared with ER-[alpha] (Cowly 2006).

The isoflavones in particular have shown the ability to reduce breast cancer risk by affecting the endogenous sex hormone concentration, influencing cancer growth through effects on estrogen receptors, inhibition of tyrosine and inhibition of angiogenesis (Adlercreutz 2004). By reducing the concentration of circulating free 'active' hormones, the isoflavones play a significant role in inhibiting the progression of breast cancer.

Highly reactive oxygen species have been shown to play a role in the development of cancer and several studies have shown that phytoestrogens can act as antioxidants, although the concentrations at which antioxidant activity is observed are unlikely to be reached through dietary means (Harper 1999). There is growing evidence that phytoestrogens could have a protective effect on the initiation or progression of breast cancer by inhibiting the local production of estrogens from circulating precursors in breast tissue. Once ingested, phytoestrogens interact with many of the same enzymes as endogenous estrogens and have been shown to interfere with the process of estrogen metabolism (Bardin 2004). Most importantly one of the most potent effects of phytoestrogens is their ability to inhibit the sulphotransferases. Circulating steroid sulphates are thought to be the major source of estradiol in postmenopausal breast tumours and sulphation is a key step in the activation of some dietary pro-carcinogens (Kirck 2001).

A large number of research studies on the effects of phytoestrogens on breast cancer tend to conclude that they inhibit cell signalling pathways. For example genistein is an inhibitor of protein tyrosine kinase (Wei 1995). At high doses genistein has been found to inhibit AP-1 transcription factor activity and induce apoptosis in breast cancer cell lines. Genistein pre-treatment inactivates NK-kB and may inhibit growth and increase apoptosis induced by chemotherapeutics such as cisplatin, docetaxel and doxorubicin (Hieh 1998). Apigenin and quercetin are inhibitors of the phosphatidyl inositol kinase (PI3K) pathway (Jeong 1999). Studies show that both compounds inhibit E2-induced DNA synthesis and proliferation of ER-positive and ER-negative breast cancer cells (Collins-Burow 2000). Resveratrol has been reported to inhibit SRC tyrosine kinase and block Stat 3 activation in malignant cells (Miodini 1999) and may modulate breast tumour growth. Both RAS/RAF/MEK/ERK (a signalling pathway associated with cell proliferation, differentiation and apoptosis) and PI3K/AKT/mTOR (an intracellular signalling pathway important in apoptosis) can be activated by growth factors and phytoestrogens may modulate the control of breast tumour growth. In addition recent studies have shown that resveratrol modulates the PI3K pathway through an ERa-dependent mechanism (Brooks 2005). Although some kinetic studies show that phytoestrogens may bind competitively with steroid substrates to inhibit steroidogenic enzymes, other evidence shows they can alter enzyme expression (Whitehead 2006). Indeed recent studies have shown that certain phytoestrogens and low dose mixtures of phytoestrogens are potent inhibitors of aromatase expression (Whitehead 2006).

Breast Cancer

Breast cancer is the most common type of cancer in the general population and the second leading cause of cancer death in Australian women. About 5% of newly diagnosed cases of breast cancer are metastatic and 30% of treated patients have a systemic recurrence. Once metastatic disease develops, the possibility of a cure is very limited with the five year survival rate at about 20% and the median survival duration varying from 12 to 24 months (Adlercreutz 2003). Estrogens may bind to two types of receptors in target cells: estrogen receptor-alpha (ER-alpha) and ER-beta, both of which can transactivate gene expression in target cells. Breast cancer cells express very high amounts of ER-alpha and far less ER-beta.

Breast cancer is not a single disease, but a collection of diseases that have distinct histopathology features, genetic and genomic variability as well as diverse prognostic outcomes. Although no individual model would be expected to completely encompass this complex disease, there is consensus amongst the researchers on the commonality of certain specific conditions that increase a woman's chance of developing breast cancer, whether it is an inflammatory breast cancer or a tubular carcinoma (Mumber 2007):

* Age: Studies show that the risk of breast cancer increases with age. This disease is uncommon in women under the age of 35. Most breast cancers occur in women over the age of 50 and the risk becomes higher above the age of 65.

* Race: Breast cancer occurs more commonly in Caucasian women as compared with African, American and Asian women.

* Personal history: Women who have suffered with cancer in one breast have a higher risk of developing cancer in the other breast compared with women who have never had cancer.

* Family history: The risk of developing breast cancer is higher if the women in any family (mother, sister and daughter) have also contracted breast cancer.

* Certain breast changes: Having a diagnosis of atypical hyperplasia or lobular carcinoma in situ (LCIS) may increase a woman's risk at a young age.

* Genetic alteration: Changes in certain genes (BRA1, BRA2 and others) increase the risk of breast cancer. However 25% of BRAC-positive patients never develop breast cancer. In families where many women have had the disease, gene testing can sometimes show the presence of specific genetic changes that increase the risk of breast cancer.

Evidence suggests that another highly significant factor associated with an increased risk for breast cancer is the length of exposure of the patient to estrogen, whether it is made by the body, taken as a drug or delivered by a patch. As estrogens are known to be potent mitogens in mammary epithelial cells, regulating estrogen metabolism is of prime importance in treatment of breast cancer. The incidence rate of breast cancer continues to increase with age despite the loss of ovarian hormones in postmenopausal women (Geller 2005). This apparent paradox has been resolved by the fact that extragonadal sites, including breast, brain, muscle, skin, bone and adipose tissue, can synthesise potent androgens and estrogens from relatively inactive circulating steroid precursors derived from the adrenal cortex and to a much lesser extent the ovaries. Indeed after menopause nearly 100% estrogens are formed in peripheral tissues and exert their effects locally in a paracrine or intracrine manner.

In postmenopausal women the concentration of 17-beta-estradiol (E2) present in breast tumours is at least 20-fold higher than that in circulation, but in premenopausal women with carcinoma this ratio was only 5-fold. This suggests that particularly in postmenopausal breast cancer, local estrogen biosynthesis is predominant (Adlercreutz 2004).

Estrogens are believed to contribute to tumour growth by promoting the proliferation of cells with existing mutations and/or by increasing the opportunity for mutations (DeLemos 2001). There are several enzymes and receptors involved in the estrogen pathway that have been suggested to play a role in the development of breast cancer. These are:

* 17-beta-hydroxysteroid dehydrogenase 1 (HSD17B1), the enzyme responsible for the conversion of estrone (E1) to estradiol (E2) which is the most potent estrogen. In human breast cancer, HSD17B1 is expressed in proliferative disease. These enzymes catalyse the interconversion of relatively inactive 17[beta]-keto steroids (e.g. androstenedione and estrone) and active 17[beta]-hydroxysteroids, such as testosterone and estradiol (Collins-Burow 2000).

* The aromatase enzyme, CYP19, a key enzyme in the conversion of androgens to estrogens. Over 60% of breast carcinomas express this enzyme (Harris RM 2004) with higher levels of mRNA expression and activity compared with non-malignant tissue (Sanderson 2004).

* Cytochrome P450 1B1 (CYP1B1) catalyses the conversion of estrone and estradiol to potentially carcinogenic catechol estrogen 4-hydroxyestrogen (4-OH). This enzyme is expressed in the mammary glands, ovary and uterus. Over-expression of this enzyme has been associated with an increased risk of breast cancer (Kirk 2005).

* 3[beta]-hydroxysteroid dehydrogenase: In relation to breast cancer this enzyme has received little attention. There are two isoforms, 1 and 2, the latter being mainly expressed in the adrenal glands and gonads and type 1 being expressed in the placenta and other tissues including skin and breast where it is considered mainly to convert DHEA to androstenedione (Gallo 2006).

* Catechol-O-methyltransferase (COMT) enzyme which is principally responsible for both the inactivation and detoxification of carcinogenic catechol estrogens. This enzyme is ubiquitous and is found in many tissues including the uterus, liver, kidney, breast, lymphocytes and erythrocytes (Lavigne 1997).

* Hyperhomocysteinemia can create a pathogenic effect largely through metabolic accumulation of intracellular S-adenosyl-L-homocysteine. The inhibition of the methylation metabolism of catechol estrogens of which this is a marker, would facilitate the development of estrogen induced hormonal cancer (Wu 2002).

The four main classes of compounds recognised as phytoestrogens, the isoflavones, coumestans, lignans and stillbenes (Caltagirone 2000), exert the unique quality of being estrogen agonist and antagonist (Barnes 2004). As agonists, phytoestrogens exert a protective effect against cardiovascular disease, menopausal symptoms (including osteoporosis) and cancer.

Conclusion

Of all the isoflavones, genistein is still attracting the most attention because of its estrogenic and antiestrogenic effects which, at high concentration, have shown inhibition on cancer cell lines through the modulation of the transforming growth factor (TGF) (Kim 1998). Genistein's greater affinity as a ligand for ER-beta than ER-alpha, suggest that it has potentially significant therapeutic actions. Interestingly this receptor shows a different anatomical distribution from ER-a, being expressed more prominently in tissues such as breast, prostate and urinary tract (Kuiper 1997). Apigenin and quercetin inhibit melanoma growth and metastatic potential.

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Manuela Malaguti-Boyle PhD Scholar ND BA BHSc (CompMed) Post Grad Nut Med Adv Dip Nat
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Author:Malaguti-Boyle, Manuela
Publication:Australian Journal of Herbal Medicine
Article Type:Report
Geographic Code:8AUST
Date:Dec 1, 2012
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