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Estrogens, BRCA1, and Breast Cancer1

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Estrogens, BRCA1, and Breast Cancer1 [CANCER RESEARCH 60, 4993–5001, September 15, 2000] Review Estrogens, BRCA1, and Breast Cancer1 Leena Hilakivi-Clarke2 Lombardi Cancer Center, Georgetown University, Washington, D.C. 20007 Abstract breast tumor development (6). However, it is not clear that there is a correlation between high estrogen exposure and high breast cancer Findings obtained in in vitro assays and animal studies indicate that risk during the years when women have functional ovaries. In fact, an estrogens might influence the activity of the tumor suppressor gene increase in breast cancer risk may be seen after a modest reduction in BRCA1, and BRCA1 in turn may suppress the activity of the estrogen receptor. This review will discuss the possibility that interactions between circulating estrogens, such as that produced by unilateral ovariectomy estrogens and BRCA1 partly explain why elevated circulating estrogen (4, 5), oral contraceptive (7, 8) or contraceptive depot use [both of levels appear to increase breast cancer risk among postmenopausal which inhibit ovulation and ovarian estrogen production (9, 10)], or women but not among young women. A hypothesis is proposed that low body weight and low fat intake (11–14). In contrast, an increase estrogens have a dual role in affecting breast cancer risk. In young women in exposure to circulating estrogens during premenopausal years whose breasts have not yet accumulated critical mutations required for caused by several pregnancies (15), short menstrual cycle length (16, cancer initiation and promotion, activation of BRCA1 by estrogens helps 17), high BMI (18), or a high fat intake (11) may reduce the risk of to maintain genetic stability and induce differentiation, and therefore developing breast cancer. High BMI or fat intake are indirect indica- estrogens do not increase breast cancer risk. Breasts of older women, in tors of increased estrogenicity: a considerable amount of estrogen contrast, are likely to contain transformed cells whose growth is stimu- lated by estrogens. Although BRCA1 is also probably activated by estro- production occurs in adipose tissue, which is a site for conversion of gens in older women, its function may have been impaired, for example, adrenal androgens to estrogens, particularly in prepubertal girls and due to increased methylation associated with aging. Estrogen exposure in postmenopausal women. women who carry germ-line mutations in BRCA1 may always increase A hypothesis is proposed here that estrogens might play a dual role breast cancer risk because estrogens would be able to cause DNA damage in affecting breast cancer risk. On one hand, there is evidence to and increase genetic instability without being opposed by BRCA1-induced indicate that estrogens might serve as preinitiators, initiators, and repair activity. This might lead to an increase in the number of overall promoters of breast cancer. We generally associate estrogens with mutations, including those that initiate breast cancer. In addition to promotion of the growth of existing malignancies in the breast (Fig. increasing genetic instability, reduced BRCA1 activity may also be linked 1). However, these hormones and their metabolic products are also to changes in the mammary gland morphology that predispose individuals to breast cancer. For example, a persistent presence of lobules type 1, shown to induce direct and indirect free radical-mediated DNA dam- which are the least differentiated lobular structures in the human breast, age, genetic instability, and mutations in cells in culture and in vivo is seen in the BRCA1 mutation carriers. The aim of this review is to (19), suggesting a role for estrogens in cancer initiation. Furthermore, discuss the role of premenopausal estrogens in breast cancer and to estrogens may serve as preinitiators. For example, elevated fetal initiate more research that would lead to novel means of reducing breast estrogen levels can permanently alter the morphology of the mam- cancer risk, particularly among BRCA1 mutation carriers. mary gland (20) and cause a persistent presence of epithelial struc- tures (TEBs) that are known to be sites of malignant growth (21). Data Introduction obtained in animal models and indirect evidence in humans indicate that high in utero estrogenicity increases breast cancer risk (20, The role of estrogens in affecting breast cancer risk during pre- 22, 23). menopausal years has remained largely unknown. Several factors In contrast to these adverse effects of estrogens on the breast, in related to reproduction appear to predispose women to breast cancer. certain circumstances, such as during pregnancy that occurs before For example, women with early onset of menarche (menstruation age 20 years (1, 15, 24) and during the prepubertal period and begins at Ͻ12 years) or late menopause (menopause occurs after 55 childhood (11, 14, 25), estrogens actually reduce breast cancer risk. years) have an increased risk of developing breast cancer (1). These The reduced risk could be achieved through estrogen-induced activa- findings suggest that the longer the exposure to ovarian estrogens, the higher the risk. This view is supported by the fact that surgically tion of certain tumor suppressor genes, including BRCA1 (26–28) induced menopause before age 45 years and the resulting removal of and p53 (29) that are critical in DNA damage repair and in maintain- ovarian estrogens markedly reduce breast cancer risk (2–5). Further- ing genetic stability, thus reducing the likelihood that breast cancer more, the partial ER3 agonist tamoxifen, which blocks the actions of will be initiated. The interaction between estrogens and tumor sup- estrogens in the breast, effectively prevents primary and recurring pressors might be important during the early reproductive years, when the breast does not yet contain any malignancies. Once breast cancer initiation has taken place, estrogens might promote the growth of Received 12/16/99; accepted 7/20/00. The costs of publication of this article were defrayed in part by the payment of page transformed cells, leading to the development of detectable breast charges. This article must therefore be hereby marked advertisement in accordance with cancer. Because estrogens increase BRCA1 expression in human 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by grants from the American Cancer Society, the American Institute for breast cancer cells in vitro (27, 28), they are also likely to do so in Cancer Research, Cancer Research Foundation of America, the Susan G. Komen Breast women whose breast contains malignant cells. However, given that Cancer Foundation, and the Department of Defense. breast cancer initiation has already occurred, the function of one or 2 To whom requests for reprints should be addressed, at Research Building, Lombardi Cancer Center, Room W405, Georgetown University, 3970 Reservoir Road NW, Wash- more tumor suppressors may be impaired at this point (failure in ington, D.C. 20007-2197. Phone: (202) 687-7237; Fax: (202) 687-7505; E-mail: tumor suppressor gene function is believed to contribute to cancer [email protected]. 3 initiation). In women carrying a mutated BRCA1 gene, estrogens may The abbreviations used are: ER, estrogen receptor; BMI, body mass index; E2, estradiol; TEB, terminal end bud; PAH, polycyclic aromatic hydrocarbon. always induce genetic instability because the mutated BRCA1 is 4993 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2000 American Association for Cancer Research. ESTROGENS, BRCA1, AND BREAST CANCER exists that activates DNA repair pathways to respond to the genomic damage initiated by estrogens and that may also occur during rapidly proliferating states. In addition, these genes that are activated by estrogens may also directly regulate the ER, perhaps by suppressing its activity. We propose that a network of normal tumor suppressor genes is activated by estrogens, which then protect the breast from an estrogen-induced increase in genetic damage and, ultimately, from neoplastic changes. Candidate estrogen-regulated tumor suppressor genes are BRCA1 and p53. Breast Cancer Susceptibility Gene BRCA1 Breast cancer is heritable in certain families. In some of these families, a breast cancer susceptibility locus on human chromosome 17q has been identified (40, 41). This locus codes for a tumor suppressor protein BRCA1. Mutations in BRCA1 account for at least 50% of inherited breast cancers and approximately 5% of all breast Fig. 1. Estrogens may increase breast cancer risk by acting as a preinitiator (if the cancer cases (40). exposure occurs during fetal life), an initiator (by inducing direct or indirect free radical- mediated DNA damage), or a proliferator (stimulating the growth of existing malignant A murine equivalent to human Brca1, Brca1, is expressed in a wide cells in postinitiated breast). The proposed mechanisms by which in utero estrogen variety of tissues, including the breast (26). The level of expression is exposure increases breast cancer risk include a persistent presence of mammary epithelial structures that serve as sites of tumor initiation and changes in the pattern of expression highest in tissues containing rapidly proliferating cells that are also of genes that are relevant to breast cancer. involved in differentiation. In mice, Brca1 is expressed broadly during embryogenesis, whereas after birth, the expression shifts to a more tissue-specific pattern (26). High levels of Brca1 mRNA can be unable to correct genetic alterations.
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