5

Examining Mechanisms of
Breast Cancer Over the Life Course:
Implications for Risk

The preceding chapters have summarized the available evidence for the relationship between environmental exposures and breast cancer, as well as the many challenges inherent in studying this issue. Although there is strong evidence of a modest role for a handful of modifiable environmental exposures as risk factors for breast cancer, many unanswered questions remain. These unanswered questions require new research approaches, which are discussed in Chapter 7.

Meanwhile, remarkable progress has been made in understanding the fundamentals of carcinogenesis, manifested in mechanisms at the genetic, epigenetic, cellular, and tissue levels. Scientific advances are revealing complex potential pathways and factors involved in cancer development. The committee sees the need for a continued and intensified focus on understanding the basic biology of breast carcinogenesis in order to gain better fundamental appreciation of the environmental factors with potential roles in the etiology of this disease.

As a crucial dimension of this research, the committee notes a growing appreciation among researchers of the important role that the timing of exposure plays in effecting changes that alter the likelihood for cancer and other diseases later in life. Observations in human studies of the effects of exposure to ionizing radiation and diethylstilbestrol (DES) in early life, as well as mechanistic and animal studies of other environmental exposures, suggest that existing assessments of the role of certain environmental factors derived from studies in adult women, such as those reviewed in Chapter 3, may have been negative or uninformative because they failed to consider critical periods of life stage and exposure—essentially asking the wrong



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5 Examining Mechanisms of Breast Cancer Over the Life Course: Implications for Risk T he preceding chapters have summarized the available evidence for the relationship between environmental exposures and breast can- cer, as well as the many challenges inherent in studying this issue. Although there is strong evidence of a modest role for a handful of modifi- able environmental exposures as risk factors for breast cancer, many unan- swered questions remain. These unanswered questions require new research approaches, which are discussed in Chapter 7. Meanwhile, remarkable progress has been made in understanding the fundamentals of carcinogenesis, manifested in mechanisms at the genetic, epigenetic, cellular, and tissue levels. Scientific advances are revealing com- plex potential pathways and factors involved in cancer development. The committee sees the need for a continued and intensified focus on under- standing the basic biology of breast carcinogenesis in order to gain better fundamental appreciation of the environmental factors with potential roles in the etiology of this disease. As a crucial dimension of this research, the committee notes a growing appreciation among researchers of the important role that the timing of exposure plays in effecting changes that alter the likelihood for cancer and other diseases later in life. Observations in human studies of the effects of exposure to ionizing radiation and diethylstilbestrol (DES) in early life, as well as mechanistic and animal studies of other environmental exposures, suggest that existing assessments of the role of certain environmental factors derived from studies in adult women, such as those reviewed in Chapter 3, may have been negative or uninformative because they failed to consider critical periods of life stage and exposure—essentially asking the wrong 239

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240 BREAST CANCER AND THE ENVIRONMENT question. As understanding grows of how the genetic, epigenetic, cellular, and tissue changes in the breast during development and over the life course influence susceptibility to breast carcinogenesis, researchers have continuing and increased appreciation for the potential for timing of exposure to make a difference in the effects of environmental agents on breast cancer risk. The committee sees the need to direct attention to the accumulating evidence that environmental exposures may have a differential impact, depending on their timing during the life course. ENVIRONMENTAL EXPOSURES OVER THE LIFE COURSE AS DETERMINANTS OF BREAST CANCER RISK The female breast is not static; it changes in structure and function over the life course. Breast development begins in utero and continues into adulthood, with further differentiation occurring with pregnancy and lac- tation and involution occurring with menopause (Russo and Russo, 2004; Polyak and Kalluri, 2010). Most breast cancers arise in and spread from the ducts or the lobules, which are the breast’s main functional components (Figure 5-1). The sections that follow consider the major life stages for women and the state of breast tissue during each stage, with indications of the potential for exposures during each stage to alter risk for breast cancer. Although evidence from human studies is limited, studies in animal models strongly indicate the potential for timing of environmental exposures to alter risk for developing cancer. Box 5-1 lists the life stages discussed by the committee and mechanisms of carcinogenesis likely to be of particular relevance or importance to breast cancer. Early Life Exposures and Breast Cancer Risk Preconceptional and Periconceptional Exposure Preconception studies focus on parental exposure to environmental agents before the conception of offspring. There is no standard definition for the preconceptional period, and the term is used rather loosely. Some studies combine the time before conception with early pregnancy as the periconceptional period (Van Maele-Fabry et al., 2010). Studies examin- ing pre- or periconceptional exposures may consider paternal or maternal exposure, or both. To date, epidemiologic studies have not addressed parental exposure before conception and subsequent risk of breast cancer in offspring. How- ever, childhood cancers, such as leukemia and brain tumors, have been linked to prenatal exposures such as maternal smoking, ionizing radiation,

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241 EXAMINING MECHANISMS OF BREAST CANCER (a) Lobules Lobe Ducts Nipple Areola Fat DCIS Wall of duct Invasive cancer cells Wall of duct (b) (c) FIGURE 5-1 Schematic representation of (a) the breast, showing lobules and ducts, (b) ductal carcinoma in situ (DCIS), and (c) invasive ductal cancer. SOURCE: NCI (2009). Figure 5-1 demonstration of a,b,c combined.eps 3 bitmaps, mask, vector labels abc and pesticides (Shim et al., 2009; Van Maele-Fabry et al., 2010). Preconcep- tional parental exposure to ionizing radiation was not associated with an increased risk of childhood leukemia (Wakeford, 1995), and parental expo- sure electromagnetic fields before conception has not been demonstrated to increase the risks of childhood cancers of any kind (Sorahan et al., 1999). It is difficult for studies to track offspring of parents whose exposures before the child’s conception are known until the children reach the ages in which breast cancer tends to manifest itself, making this a potential area for future research. In Utero and Neonatal Exposure The human breast begins to develop once the embryo reaches 4.5–6 mm in length (Hughes, 1950). Embryonic epidermal cells proliferate to cre- ate a breast bud, which responds to cues from the embryonic mesenchyme (Anbazhagan et al., 1998). In the newborn human, the breast is character- ized by “very primitive structures, composed of ducts ending in short duct-

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242 BREAST CANCER AND THE ENVIRONMENT BOX 5-1 L ife Stages Representing Potential Windows of Susceptibility for Breast Carcinogenesis and Hypothesized Mechanisms of Carcinogenesis Some mechanisms are likely to be more relevant or important to breast carcinogenesis at particular life stages (e.g., epigenetic reprogram- ming during the in utero/perinatal period). Life Stages as Potential Hypothesized Mechanisms of Windows of Susceptibility Carcinogenesis • Preconception • Mutagenesis • In utero/perinatal • Nuclear hormone receptor signaling • Early childhood • Mitogenic signaling leading to cell • Prepuberty proliferation • Puberty • Epigenetic and developmental • Reproductive years reprogramming • Menopause • Modulation of immune function, • Postmenopausal years escape from immune surveillance • Alterations of tissue microenvironment ules lined by one to two layers of epithelial and one of myoepithelial cells” (Russo and Russo, 2004, p. 3). The breast in the newborn also contains a population of stem cells that are the undifferentiated precursors of the cel- lular expansion that occurs as the structures of the breast develop during puberty, pregnancy, and lactation. Strong evidence indicates that aspects of fetal growth, such as birth weight, are associated with breast cancer risk as an adult (Potischman and Troisi, 1999; Michels and Xue, 2006; dos Santos Silva et al., 2008; Park et al., 2008b). According to one postulation advanced by Trichopoulos and others (2005), the number of mammary stem cells is determined during in utero or immediate postnatal life and is under the influence of estrogens and components of the insulin-like growth factor system during pregnancy. They hold that the number of mammary tissue-specific stem cells is the core determinant of breast cancer risk. Thus, an increase in mammary stem cells associated with higher birth weight would provide more target cells for breast carcinogenesis. This postulation also includes recognition of the increased risk of breast cancer associated with increased breast density and mass of glandular tissue (Boyd et al., 1998, 2010), which is itself likely linked to the number of stem

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243 EXAMINING MECHANISMS OF BREAST CANCER cells (Trichopoulos et al., 2005). While this hypothesis focuses on the effects of endogenous estrogens and growth factors, it also provides a potential mechanism by which exogenous environmental agents might increase (or decrease) breast cancer risk if prenatal exposure to them promotes the for- mation of greater numbers of breast stem cells. There is growing evidence from rodent models to indicate that exposure to xenoestrogens during the prenatal and neonatal periods may affect mammary gland development and alter risk for cancer later in life (Soto et al., 2008). Some of these changes are thought to possibly result from developmental reprogramming as described below, but some of the mechanisms are just beginning to be elucidated. During gestation, while maternal levels of the pregnancy hormones progesterone and estrogen soar, the developing fetus is protected from endogenous maternal hormones by steroid hormone binding proteins. Ste- roid hormones such as progesterone and estrogen circulate in the blood stream bound to proteins such as serum albumin and sex hormone binding globulin (SHBG), which is a glycoprotein that specifically binds testosterone and estradiol. Only a small fraction of steroid hormones is present in the circulation in the unbound “free” form. In utero, the fetal liver synthesizes sufficient amounts of steroid hormone binding proteins, including steroid- binding β-globulin (SBβG) and alpha fetoprotein (AFP), to protect the developing organism from rising levels of maternal hormones. Thus, even when maternal estrogen levels are extremely high, increased expression of AFP and other steroid hormone binding proteins (Mizejewski et al., 2004) reduces the unbound fraction of estradiol in the human fetus to 1.0 to 4.5 percent (i.e., greater than 95 percent is bound) (Pasqualini et al., 1985; vom Saal and Timms, 1999; Witorsch, 2002, citing Tulchinsky, 1973). In pri- mates, fetal hormone levels actually decline in the face of increasing mater- nal hormones during pregnancy (Thau et al., 1976). Production of steroid hormone binding proteins by the fetal liver decreases dramatically after birth. Thus, some free endogenous steroid hormone is likely to come in contact with developing tissues of the fetus. In the context of environmental exposures, however, in vitro studies with human serum (e.g., Milligan et al., 1998; Jury et al., 2000) and in vivo studies in mice (Welshons et al., 1999) have found that various xenoestrogens are generally not recognized by these steroid hormone binding proteins. As a result, the mechanism that limits fetal exposure to endogenous estrogens may offer less protection from these xenoestrogens. One of the best known examples in humans of an in utero exposure altering risk for cancer later in life is that of DES. Between 1938 and 1971, this estrogenic compound was used to prevent miscarriages, but it was taken off the market when daughters of women who took it during pregnancy developed adenocarcinomas of the vagina (Herbst et al., 1971).

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244 BREAST CANCER AND THE ENVIRONMENT Long-term follow-up studies of both mothers and their offspring have found that daughters who were exposed to pharmacological levels of DES in utero experienced important and devastating effects on adult health many years later, including an elevated risk of breast cancer (Palmer et al., 2006; Troisi et al., 2007). These studies have graphically demonstrated that the period of organogenesis during fetal life is a period when humans may be particularly sensitive to the effects of environmental agents—in this case synthetic estrogens. From an epidemiologic standpoint, these DES studies have provided a unique illustration of early development as a window of susceptibility to environmental exposures in terms of the clarity of the dose and timing of the exposure and the extremely long and costly period of follow-up. Studies in Sprague Dawley rats exposed perinatally to 1.2 µg of DES by subcutaneous injection have demonstrated increased susceptibility to mammary carcinogenesis after postnatal treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) (Boylan and Calhoon, 1979, 1983). A higher incidence of palpable tumors and decreased tumor latency were observed compared with DMBA-treated rats without prior hormone exposure (Boylan and Calhoon, 1979, 1983); however, major differences in reproductive tracts or mammary gland structure were not observed at the DES doses used (Boylan and Calhoon, 1983). Kawaguchi et al. (2009a) also used Sprague Dawley rats to demonstrate that rats that had prenatal exposure to DES (their mothers had been fed DES [0.1 ppm] throughout pregnancy or from day 13 of pregnancy through to birth) and were then exposed to DMBA at 50 days after birth developed more mammary carci- nomas than controls. Experiments in ACI rats without additional carcinogen dosing demon- strated that mammary tumors can be induced in female rats by prenatal (0.8 µg or 8.0 µg s.c. to the pregnant mother, equivalent to 4.28 µg/kg or 42.8 µg/kg of body weight) or postnatal (2.5 mg via implanted pellet) DES exposure alone, and that prenatal and postnatal DES exposure combined yielded significantly greater tumor multiplicity and decreased tumor latency (Rothschild et al., 1987). The morphology of peripubertal mammary glands of a significant proportion of female ACI rats exposed to DES in utero were atypical; approximately 25 percent displayed hypodifferentiation and about 5 percent had hyperproliferation (Vassilacopoulou and Boylan, 1993). In utero DES exposure is theorized to increase mammary cancer suscep- tibility by slowing mammary gland maturation and development (Jenkins et al., 2011).The most mature structures of the mammary gland, lobules, appear to be most resistant to carcinogenic transformation by chemical carcinogens, while terminal end buds are more susceptible (Russo and Russo, 1978; Russo et al., 1982). Prenatal DES exposure has been reported to increase the number of terminal end buds, increasing susceptibility to

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245 EXAMINING MECHANISMS OF BREAST CANCER chemical carcinogenesis (Ninomiya et al., 2007). In contrast to the effects from fetal exposure to DES, exposure to DES at other time windows has been shown to manifest different effects (Lamartiniere and Holland, 1992; Hovey et al., 2005; Kawaguchi et al., 2009b). Studies carried out to explore the mechanisms of uterine estrogenic effects from perinatal exposure to DES in the CD-1 mouse model might prove helpful for understanding effects in the mammary gland. Estro- genic effects include persistent expression of the lactoferrin and c-fos genes (Newbold et al., 1997; Li et al., 2003) together with a high incidence of uterine adenocarcinoma (Newbold et al., 1990). DES exposure also causes changes in the expression of several uterine genes responsible for directing tissue architecture and morphology, resulting in altered tissue structures (Ma et al., 1998; Miller et al., 1998; Block et al., 2000). Thus, altered gene expression, likely as a result of epigenetic reprogramming, may also be a contributor to increased susceptibility to mammary carcinogenesis in DES-exposed animals. The body of animal studies carried out with DES demonstrates that the in utero and neonatal periods are especially vulner- able to inappropriate xenoestrogen exposure, with these exposures inducing developmental reprogramming and potentially altering risk for cancer later in life. Although intentional human exposures to pharmacologic doses of estrogen compounds such as DES are hopefully unlikely to recur, exposure to environmental chemicals with estrogen-like activity is common. Analy- sis of data from the National Health and Nutrition Examination Survey (NHANES) 2003–2004 found a large range of chemicals present in blood or urine in women who were and were not pregnant (Woodruff et al., 2011). Concentrations tended to be similar or lower in pregnant women compared to those in women who were not pregnant. The analysis demonstrates the potential opportunity for exposure of the developing fetus and the pregnant mother’s breast to a wide range of chemical compounds. Whether or not the presence of these chemicals is associated with an increased risk of breast cancer in either child or parent requires additional investigation. Early Childhood and Prepuberty The rudimentary ductal system present in the breast at birth is under the influence of maternal hormones (Anbazhagan et al., 1991). But by age 2, the breast undergoes involution, and it has only a primitive ductal system without alveoli until the onset of puberty (Howard and Gusterson, 2000). During this period, however, the body is preparing for puberty and the next stage of mammary gland development. Various exposures during childhood appear to influence the timing of puberty. Because the timing of puberty is associated with the risk of breast cancer later in life, better understanding

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246 BREAST CANCER AND THE ENVIRONMENT of the factors in childhood that influence the timing of puberty may add to understanding of pathways that can contribute to breast cancer. Diet and the nutritional content of food consumed in childhood help set the stage for puberty by developing adequate body mass. However, prepubertal overweight and obesity are positively associated with early puberty (Kaplowitz, 2008) and late pubertal peak height velocity and early menarche (Hauspie et al., 1997). Recent national health surveillance data for the United States show that 35 percent of girls ages 6–11 are at or above the 85th percentile of body mass index (BMI) standards for their age, and 18 percent are at or over the 95th percentile (Ogden et al., 2010). Biro and colleagues (2003, 2010) have shown that girls with higher BMIs are likely to begin puberty at an earlier age. However, the mechanism underlying the association between obesity and earlier puberty is not yet clear (Jasik and Lustig, 2008). The impact of decreased physical activity, independent of energy intake, and its effects in different subgroups of children in this prepubertal period may act through decreased insulin sensitivity and are also of concern (Sorensen et al., 2009). Further investigation is needed to understand the relation between activity levels in childhood and the timing of puberty or other factors that may influence breast cancer risk in later life. Psychosocial factors have also been found to influence pubertal timing among girls (Graber et al., 1997; Ellis and Garber, 2000; Bogaert, 2005). They are likely to operate through pathways other than diet, physical activ- ity, and obesity. In stressful family contexts, characterized by low-quality parental investment, high levels of stress, negative relationships, and pro- longed distress, reproductive maturation appears to accelerate (Romans et al., 2003). Family relationships characterized by warmth, cohesion, and sta- bility, on the other hand, consistently predict later pubertal onset (Graber et al., 1995). One particular manifestation of disrupted family relationships exists in households with the absence of a biological father. Studies have shown an association between early pubertal maturation in both boy and girl twins in homes where the father was absent when the children were age 14. Girls were about twice as likely to experience menarche before age 12 in such households, although the mechanisms for this observation are not clear (Quinlan, 2003; Mustanski et al., 2004). One study has found this relationship confined to white girls in families with higher socioeconomic status, as measured by household income (Deardorff et al., 2011). Overall, a review of the father-absence literature suggests that girls in father-absent homes experience menarche 2 to 5 months earlier than those in homes where the father is present (Ellis, 2004). The absence of the mother or the presence of a stepfather does not appear to be related to pubertal timing (Bogaert, 2005). Animal studies suggest that endocrine-disrupting chemicals (EDCs) may alter hormone synthesis and metabolism during this prepubertal period

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247 EXAMINING MECHANISMS OF BREAST CANCER (Crain et al., 2008) and may advance the onset of puberty. Individual nutrients and dietary intake of substances such as phytoestrogens, which are considered xenoestrogens, may also be factors in pubertal develop- ment. In a study of pubertal development in 9-year-old girls, higher urinary concentrations of phytoestrogens, and in particular daidzein and genistein, were associated with later age of breast development, and this effect was stronger in girls with lower BMIs (Wolff et al., 2008). The delay in pubertal development is considered protective in terms of risk for breast cancer. A limited set of case–control studies provides some support for an association between higher consumption of soy products during childhood and lower risk of breast cancer (reviewed in Hilakivi-Clarke et al., 2010). Studies in animal models of genistein exposure have investigated the importance of the timing of exposures in altering mammary tumor sus- ceptibility. The animal data regarding postnatal, prepubertal exposure to genistein are described as “very consistent” in showing a reduction in mammary cancer risk (Warri et al., 2008). In early studies, Lamartiniere and coworkers (1995) observed that rats treated with genistein during the early postnatal period displayed increased mammary tumor latency and decreased tumor multiplicity in classic chemical carcinogenesis models. In contrast, animal studies of in utero genistein exposure have produced conflicting results (reviewed in Warri et al., 2008). Differences in the impact of pre- and postnatal exposures in these animal models highlight the potential for the timing of human exposure to genistein, and likely other xenoestrogens, to have differing impacts on breast cancer risk. Puberty and Adolescence The onset of puberty, the pubertal period, and adolescence comprise another life stage during which environmental factors may influence the development of breast cancer in adult life in unique ways. This stage spans the period from the first signs of sexual development and the external appearance of the breast to sexual maturity (Russo and Russo, 2004). Breast development in adolescent girls is characterized by branching of terminal end buds in response to hormonal cues (Russo and Russo, 2004). The onset of puberty is clinically defined by the first signs of breast development, pubic hair, and other secondary sex characteristics (Grumbach and Styne, 2002). It coincides with the activation of the hypothalamic– pituitary–gonadal (HPG) axis, or thelarche, and the activation of the hypothalamic–pituitary–adrenal (HPA) axis, or adrenarche, which are inde- pendent events. HPG axis activation is associated with a surge of pituitary follicle-stimulating hormone (FSH), which results in the stimulation of primordial ovarian follicles to secrete estrogen. Circulating estrogen then

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248 BREAST CANCER AND THE ENVIRONMENT has several important effects, including the release of pituitary luteinizing hormone (LH) and vascular proliferation and growth in the breast with the further development of the mammary ducts and the mammary stromal con- nective tissue (Rogol, 1998). The activation of the HPA axis stimulates the adrenal production of dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione, which lead to the development of secondary sexual characteristics, including pubic hair and changing body proportions. The relative timing of thelarche and adrenache may differentially determine the onset of menarche (Biro et al., 2006). Early age at menarche is an established risk factor for breast cancer (Kelsey and Bernstein, 1996), but its use as a marker of pubertal onset can be misleading because the relationship between the onset of puberty and menarche has not been constant over time (Euling et al., 2008; Mouritsen et al., 2010). In the United States, the correlation between the onset of puberty and menarche was greater than 0.9 for women born in the 1930s, 0.5–0.7 for those born in the 1950s, and 0.38–0.39 for those born in the 1970s (Biro et al., 2006). These results suggest that factors contributing to the onset of puberty and menarche were more similar in the past than in more recent years. Clear differentiation between the time of onset of puberty and menarche and the interval between them (“tempo”) is important in studies of pubertal development (Euling et al., 2008). It is clear that both the age when girls begin puberty and their age of menarche have declined over the past century (Euling et al., 2008). How- ever, historical data and more recent detailed epidemiologic studies have concluded that the age of menarche declined in industrialized countries over the course of the past century, whereas the decline in the age of onset of puberty has been rapid and observed since just since the early 1990s (de Muinck Keizer-Schrama and Mul, 2001; Euling et al., 2008; Aksglaede et al., 2009; Mouritsen et al., 2010). This latter decline has not been associ- ated with development and socioeconomic conditions and has thus raised concerns about the possible role of environmental factors such as endocrine disrupting chemicals (Mouritsen et al., 2010). Genetic regulation of puberty is unlikely to explain these rapid secular trends, but genetic factors do influence the age of pubertal onset in individual girls (Parent et al., 2005). Supporting evidence comes from studies documenting a correlation between a mother’s and daughter’s ages at puberty, from twin correlation studies that suggest that most (70–80 percent) of the variance between twins is explained by genetic influences, and from the observation of marked dif- ferences in pubertal timing among racial and ethnic groups (Parent et al., 2003, 2005). At the onset of puberty, the ratio of FSH to LH favors FSH, which inhibits ovulation, and even with the onset of menarche, ovarian function can continue to be anovulatory for a time (MacMahon et al., 1982b).

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249 EXAMINING MECHANISMS OF BREAST CANCER The duration of anovulatory menstrual cycles after the onset of menarche varies from 1 to more than 6 years, with longer intervals to ovulation in girls with a late menarche (MacMahon et al., 1982a; Clavel-Chapelon, 2002). The shorter period of anovulation for girls with earlier menarche would suggest that the increased risk of breast cancer that is associated with earlier menarche may be related to earlier and more frequent expo- sure to the hormones produced during the menstrual cycle. Moreover, acceleration of menarche without a concomitant acceleration in the timing of menopause increases the duration of estrogen exposure over a lifetime, which it is widely thought to promote the development of breast cancer (de Waard and Thijssen, 2005). For each additional year of delay in men- arche, the risk of breast cancer is decreased by approximately 9 percent for premenopausal cases and by approximately 4 percent for postmenopausal cases (Hsieh et al., 1990; Clavel-Chapelon and Gerber, 2002). Among women in the Nurses’ Health Study II, who were followed between 1989 and 1993, a 1-year increase in age at menarche was associated with reduc- tion in risk of 10 percent (RR = 0.90, 95% CI, 0.83–0.99) (Garland et al., 1998). In a comparison between women with an age of menarche of 13 versus 15 years or older, an older age of menarche was associated with a statistically significantly reduced risk for premenopausal breast cancer (OR = 0.72, 95% CI, 0.57–0.91), but the reduction in risk for post- menopausal breast cancer was not statistically significant (OR = 0.90, 95% CI, 0.80–1.03) (Titus-Ernstoff et al., 1998). The contribution of timing of puberty and onset of menarche to increased breast cancer risk may be related to estrogen receptor signaling or to other mechanisms discussed later in this chapter. It is also possible that the rapidly duplicating cells of the breast during pubertal development are more susceptible to environmental insults. Studies in the rodent model show that the highest number and the greatest proliferative activity of the terminal duct lobular units (TDLUs) occurs during puberty (Rudland, 1993), and it has been suggested that this may be related to the apparent susceptibility of the breast to carcinogens during puberty (Colditz and Frazier, 1995; Knight and Sorensen, 2001). Some of the best evidence for susceptibility of breast tissue during early-life exposures is derived from investigation of the effects of ionizing radiation from nuclear explosions and from medical diagnostic and treat- ment procedures. An increased risk for breast cancer has been documented among atomic bomb survivors in Japan (Tokunaga et al., 1991), and this increased risk has been related to younger age at exposure, especially dur- ing the period of puberty (Land et al., 2003). In an ecological study of the Chernobyl accident in Belarus, the areas with the highest levels of radiation contamination (estimated average cumulative doses ≥ 40 mSv) were asso- ciated with elevated breast cancer risk about 10 years after the incident,

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