ReviewMolecular epidemiology of sporadic breast cancer: The role of polymorphic genes involved in oestrogen biosynthesis and metabolism
Introduction
Breast cancer is the prevailing cancer among women in industrialized countries [1]. Heritable factors are observed in one-fourth of breast cancer cases [2]. However, germline mutations in so-called high-penetrance cancer susceptibility genes, such as BRCA1 and BRCA2, have been shown to account for only up to 5% of all breast cancer cases [3], [4]. Therefore, relatively common genes acting together with endogenous/lifestyle risk factors (low-penetrance genes), are likely to account for a much higher portion of the breast cancer cases together with yet unidentified high-penetrance genes [5].
The molecular mechanisms underlying the development of breast cancer are not completely understood. However, it is generally believed that the initiation of breast cancer is a consequence of cumulative genetic damages leading to genetic alterations that result in activation of proto-oncogenes and inactivation of tumor suppressor genes. These in turn are followed by uncontrolled cellular proliferation and/or aberrant programmed cell death, or apoptosis. Also, the role of reactive oxygen species (ROS) has been related to the aetiology of cancer, as they are known to be mitogenic to variety of cells, and therefore capable of tumor promotion [6].
Most of the risk factors for breast cancer relate to the increased or prolonged exposure to oestrogen. The main effect of oestrogens is thought to be via stimulation of breast-cell proliferation, thereby increasing the chances that a cell bearing a potentially cancer-causing mutation will multiply [7], [8]. The initial genetic damage was previously thought to arise solely from spontaneous mutations or damage triggered by external exposures such as radiation and cigarette smoke. However, current evidence suggests that the metabolic by-products of oestrogen in the body may also act as initiators of cellular alterations [9].
Considerable inter-individual variability has been observed in carcinogen metabolism as well as in the biosynthetic pathways and metabolism of steroid hormones [10]. These person-to-person differences are largely attributed to polymorphism in the genes encoding for the xenobiotic metabolizing enzymes (XMEs). The XME gene polymorphisms may therefore define subpopulations of women with higher lifetime exposure to oestrogens, oestrogen metabolites, and other carcinogens [11]. Such variation could explain a portion of the breast cancer susceptibility associated with reproductive events and hormone exposure, as well as other lifestyle/environmental risk factors. They are therefore considered to account for a high proportion of breast cancer cases.
In this paper, we discuss the potential role of polymorphic genes coding for enzymes involved in oestrogen biosynthesis and metabolism in modulating individual susceptibility to breast cancer.
Section snippets
Descriptive epidemiology of breast cancer
With 1 million new cases diagnosed in the world annually, breast cancer is by far the most common female cancer, comprising about 20% of all new cancers in women [1], [12]. The highest age-adjusted incidence rate is reported for North America, being 86.3 per 100,000 women per year, while the lowest rate, reported in China, is only 11.8 [12]. Breast cancer follows a steeply increasing age gradient up to 50 years of age, after which the rate of increase slows down.
Even though there are three
Oestrogen
All oestrogens have an aromatic A ring, a phenolic hydroxyl group at C-3 and a methyl group at position C-13. Oestradiol (E2) with a hydroxyl group at C-17 and oestrone (E1) with a keto-group at this position, are the major oestrogens in the blood, oestradiol being biologically the most active in breast tissue [102].
Oestrogens and progesterone exert their cellular actions by forming complexes with their respective receptors [103]. The binding efficancy of oestrogen to ER is determined by its
Genetic polymorphisms in oestrogen metabolizing enzymes and breast cancer
Person-to-person differences in the conjugation pathways of both oestrogen and catechol oestrogens may define subpopulations of women with higher lifetime exposure to hormone-dependent growth promotion or to cellular damage from particular oestrogens and oestrogen metabolites. Such variation could explain a portion of the cancer susceptibility associated with reproductive events and hormone exposure. The most widely studied polymorphisms in low-penetrance genes encoding for enzymes with a
Concluding remarks
As discussed in this review, the studies conducted to date on polymorphic estrogen metabolizing enzymes and breast cancer risk have yielded contrasting results. Considerable portion of the differences are anticipated to be due to poor study designs.
Case–control studies are the most commonly used methods to seek potential associations between genetic polymorphisms and the risk of common diseases in the population, and interactions between genetic and environmental risk factors. Many of the
Acknowledgements
This work was supported by the Academy of Finland and the Finnish Konkordia Foundation.
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