Review
Molecular epidemiology of sporadic breast cancer: The role of polymorphic genes involved in oestrogen biosynthesis and metabolism

https://doi.org/10.1016/S1383-5742(03)00016-4Get rights and content

Abstract

The major known risk factors for female breast cancer are associated with prolonged exposure to increased levels of oestrogen. The predominant theory relates to effects of oestrogen on cell growth. Enhanced cell proliferation, induced either by endogenous or exogenous oestrogens, increases the number of cell divisions and thereby the possibility for mutation. However, current evidence also supports a role for oxidative metabolites, in particular catechol oestrogens, in the initiation of breast cancer. As observed in drug and chemical metabolism, there is considerable interindividual variability (polymorphism) in the conjugation pathways of both oestrogen and catechol oestrogens. These person-to-person differences, which are attributed to polymorphisms in the genes encoding for the respective enzymes, might define subpopulations of women with higher lifetime exposure to hormone-dependent growth promotion, or to cellular damage from particular oestrogens and/or oestrogen metabolites. Such variation could explain a portion of the cancer susceptibility associated with reproductive effects and hormone exposure. In this paper the potential role of polymorphic genes encoding for enzymes involved in oestrogen biosynthesis (CYP17, CYP19, and 17β-HSD) and conversion of the oestrogen metabolites and their by-products (COMT, CYP1A1, CYP1B1, GSTM1, GSTM3, GSTP1, GSTT1 and MnSOD) in modulating individual susceptibility to breast cancer are reviewed. Although some of these low-penetrance genes appeared as good candidates for risk factors in the etiology of sporadic breast cancer, better designed and considerably larger studies than the majority of the studies conducted so far are evidently needed before any firm conclusions can be drawn.

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.

References (278)

  • D. Ford et al.

    Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium

    Am. J. Hum. Genet.

    (1998)
  • V.N. Kristensen et al.

    Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism

    Mutat. Res.

    (2000)
  • K. McPherson et al.

    ABC of breast diseases, breast cancer-epidemiology, risk factors, and genetics

    BMJ

    (2000)
  • P. Lichtenstein et al.

    Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland

    N. Engl. J. Med.

    (2000)
  • D. Easton et al.

    Inherited susceptibility to breast cancer

    Cancer Surv.

    (1993)
  • S. Oesterreich et al.

    Tumor suppressor genes in breast cancer

    Endocr. Relat. Cancer

    (1999)
  • M.C. Johnson-Thompson et al.

    Ongoing research to identify environmental risk factors in breast carcinoma

    Cancer

    (2000)
  • S. Nandi et al.

    Hormones and mammary carcinogenesis in mice, rats, and humans: a unifying hypothesis

    Proc. Natl. Acad. Sci. U.S.A.

    (1995)
  • C.R. Jefcoate et al.

    Tissue-specific synthesis and oxidative metabolism of estrogens

    J. Natl. Cancer Inst. Monogr.

    (2000)
  • J.D. Yager

    Endogenous estrogens as carcinogens through metabolic activation (in process citation)

    J. Natl. Cancer Inst. Monogr.

    (2000)
  • A.M. Dunning et al.

    A systematic review of genetic polymorphisms and breast cancer risk

    Cancer Epidemiol. Biomarkers Prev.

    (1999)
  • B.E. Henderson et al.

    Hormonal carcinogenesis

    Carcinogenesis

    (2000)
  • C. Mettlin

    Global breast cancer mortality statistics

    CA Cancer J. Clin.

    (1999)
  • J.F. Dorgan et al.

    Serum sex hormone levels are related to breast cancer risk in postmenopausal women

    Environ. Health Perspect.

    (1997)
  • T.J. Key

    Serum oestradiol and breast cancer risk

    Endocr. Relat. Cancer

    (1999)
  • M. Kabuto et al.

    A prospective study of estradiol and breast cancer in Japanese women

    Cancer Epidemiol. Biomarkers Prev.

    (2000)
  • L. Bernstein et al.

    Endogenous hormones and breast cancer risk

    Epidemiol. Rev.

    (1993)
  • H.S. Feigelson et al.

    Estrogens and breast cancer

    Carcinogenesis

    (1996)
  • C.S. Berkey et al.

    Adolescence and breast carcinoma risk

    Cancer

    (1999)
  • D. Apter et al.

    Some endocrine characteristics of early menarche, a risk factor for breast cancer, are preserved into adulthood

    Int. J. Cancer

    (1989)
  • L. Bernstein et al.

    Physical exercise and reduced risk of breast cancer in young women

    J. Natl. Cancer Inst.

    (1994)
  • J.L. Kelsey et al.

    Reproductive factors and breast cancer

    Epidemiol. Rev.

    (1993)
  • B.E. Henderson et al.

    Do regular ovulatory cycles increase breast cancer risk?

    Cancer

    (1985)
  • Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative...
  • W.C. Chie et al.

    Age at any full-term pregnancy and breast cancer risk

    Am. J. Epidemiol.

    (2000)
  • D.R. Pathak et al.

    Breast carcinoma etiology: current knowledge and new insights into the effects of reproductive and hormonal risk factors in black and white populations

    Cancer

    (2000)
  • J. Russo et al.

    Developmental, cellular, and molecular basis of human breast cancer (in process citation)

    J. Natl. Cancer Inst. Monogr.

    (2000)
  • L. Lipworth et al.

    History of breast-feeding in relation to breast cancer risk: a review of the epidemiologic literature

    J. Natl. Cancer Inst.

    (2000)
  • W.Y. Huang et al.

    Hormone-related factors and risk of breast cancer in relation to estrogen receptor and progesterone receptor status

    Am. J. Epidemiol.

    (2000)
  • S.M. Enger et al.

    Body size, physical activity, and breast cancer hormone receptor status: results from two case–control studies (in process citation)

    Cancer Epidemiol. Biomarkers Prev.

    (2000)
  • D.J. Hunter et al.

    Diet, body size, and breast cancer

    Epidemiol. Rev.

    (1993)
  • W. Yue et al.

    Aromatase within the breast

    Endocr. Relat. Cancer

    (1999)
  • R. Ballard-Barbash

    Anthropometry and breast cancer. Body size—a moving target

    Cancer

    (1994)
  • S. Mannisto et al.

    Body-size indicators and risk of breast cancer according to menopause and estrogen-receptor status

    Int. J. Cancer

    (1996)
  • I.J. Hall et al.

    Body size and breast cancer risk in black women and white women: the Carolina Breast Cancer Study

    Am. J. Epidemiol.

    (2000)
  • Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative...
  • C. Schairer et al.

    Estrogen–progestin replacement and risk of breast cancer

    JAMA

    (2000)
  • J.E. Rossouw et al.

    Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial

    JAMA

    (2002)
  • S. Stallard et al.

    Effect of hormone replacement therapy on the pathological stage of breast cancer: population based, cross sectional study

    BMJ

    (2000)
  • F. Grodstein et al.

    Postmenopausal hormone therapy and mortality

    N. Engl. J. Med.

    (1997)
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