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Julius Center, Universitair Medisch Centrum Utrecht, Utrecht, The Netherlands
3To whom correspondence should be addressed. E-mail: p.a.h.vannoord{at}umcutrecht.nl.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • caloric restriction • breast cancer • set point • hypothalamus • development • hypothesis
Background
This research program was designed to determine whether the preventive effects of caloric restriction as found in rodent studies also apply to humans. In this overview, results from studies in the DOM (diagnostic onderzoek mammacarcinoom) cohort on effects of the Dutch famine of 1944–1945 on breast cancer and its risk factors are presented and put in a wider perspective. A hypothalamic set-point hypothesis that may accommodate the opposing effects observed in the different studies and relate them to prevailing notions about caloric restriction and cancer risk from a more developmental and evolutionary perspective is presented.
Animal studies. One of the most replicable methods to reduce cancer risks in rodents is postnatal long-term caloric deprivation (1,2). Apart from other effects on other chronic diseases and longevity (3), the effects on cancers seem most pronounced in their effect on hormone-dependent tumors (4,5). These effects may reflect the responses from well-preserved evolutionary mechanisms (6,7), such as those involved in the modulation of energy investment in the maintenance of the organism itself vs. investment in procreation. In the flatworm Caenorhabditis elegans such an adaptation mechanism has been linked to shifts in daf, an insulin-like growth factor-1 (IGF-1)4 related precursor that is involved in inducing the dauer state, a situation resembling hibernation (8). One suggested hormone-related mechanism in rodents that mediates such effects of caloric deprivation has been termed a pseudohypophysectomy (9). Rodent studies with pituitary isografts have stressed the importance of pituitary-mediated regulatory mechanisms and pituitary-derived hormone production in cancer studies (10–12), though the effects in the rat and the mouse models may show important differences. The most elaborate model of breast cancer in rodents is that of Russo et al. (13), where pregnancy-related placental chorionic gonadotropin plays an important role in mediating breast cancer risk.
Human studies. With respect to breast cancer, in the era before hormonal therapy, hypophysectomy alone or in combination with ovariectomy and/or adrenalectomy was one way to treat or to slow breast cancer. Caloric restriction later in life as a way to prevent or to treat being overweight has been suggested as a way to reduce the production of extraovarian estrogens in postmenopause, thereby reducing breast cancer risk (14). Longitudinal studies on the effects of caloric deprivation in humans early in life are scarce (15). The study by Susser and Stein (16,17) on the effects of the Dutch famine on brain development was the first large-scale study exploring lasting effects of intrauterine, thus prenatal, famine exposure on intelligence, and mental health. This study raised more interest within The Netherlands about the sad but unique opportunities that this historical "experiment" provides for investigating the long-term effect of caloric deprivation early in life on chronic disease risks (18–21).
Other examples of studies on the effects of postnatal reduction of caloric intake include studies on gymnastic athletes, runners, and ballet dancers. In these girls, menarche occurred later, whereas in women already menstruating, menstruations could be stopped by higher energy expenditure by increasing their level of exercise (22,23). Follow-up of these groups showed a decline in several reproductive traits, as well as their risk on reproductive cancers (24,25). Comparable effects on menstrual cycling and breast cancer risk were reported in patients with anorexia (26,27). A limitation to the generalizability of studies on athletes is that the athletes tend to represent a self-selected group, often with a specific body habitus and a more or less lifelong lifestyle whereby exercise reduces the number of calories available for growth and maturation. In anorexia patients, the cause and effect of reducing caloric intake are unclear. What seems clear is an involvement of the hypothalamic and diencephalic centers of the "old" brain that regulate appetite, body image, and reproductive factors. These parts of the brain are also involved in mediating related mechanisms operating in the terminal phase of cancer when emaciation by cachexia-anorexia occurs (28,29).
The Dutch famine of 1944–1945. One way to throw light on the issues of the role of postnatal exposure to caloric deprivation on cancer risks might be to look at the effects of exposure to the Dutch famine of 1944–1945 in the western part of The Netherlands. This famine occurred at the close of World War II. By September 1944, the allied forces had liberated the southern part of The Netherlands that lies below the Rhine. Operation Market Garden was launched to cross the Rhine at Arnhem in the eastern part of The Netherlands in an attempt to end the war. The Dutch government in exile ordered a railroad strike to sabotage the German army. Their response was a transport embargo that severely affected food transports from the more agricultural east and north of The Netherlands. When Market Garden turned out to have been "one bridge too far," the food and fuel situation deteriorated quickly. The coal-producing southern part of The Netherlands could not provide the fuel for heating and cooking, a situation that was extradramatic given that the winter that followed in 1944–1945 was unusually fierce. The western part of The Netherlands containing the 4 largest cities—Amsterdam, Rotterdam, the Hague, and Utrecht—suffered most. By the time the transportation ban was lifted, most of the alternative waterway routes had frozen, and the train system had been destroyed by allied bombardments. Thus both food and fuel distribution was limited. This situation of hunger and cold lasted until May 1945 when the rest of The Netherlands was finally liberated.
The system of food rationing had been designed before the war by the Dutch government in anticipation that The Netherlands would remain neutral, as in World War I. The Germans kept this infrastructure, including the system of public soup kitchens controlled by local authorities, during the famine (30). In addition to keeping good records about available foods (31), efforts were made to ensure as much as possible that the dietary composition of the rationing remained more or less optimal, though the amount of calories that could be provided dropped dramatically to 600 kcal/d at the peak of the famine. Thus this famine can be described as a 6-mo period (between October 1944 to May 1945) of caloric restriction. Red Cross teams that visited The Netherlands immediately after the war did not find many signs of malnutrition (beriberi, scurvy, etc.). Hence, by May 1945, the famine had not yet totally depleted the reserves of essential nutrients stored in the liver. A higher mortality was limited to elderly males and very young children. Because the women in the DOM cohorts were over 2 y old during the famine, it is unlikely that the women who could be studied in these cohorts as presented hereafter reflect a selected group of survivors. This makes the situation in The Netherlands especially unique compared with other famine-struck areas such as Leningrad during the war, and East Germany and Greece after the war, and with situations of long-term malnutrition such as still exist in the several developing countries. The Dutch famine thus is more comparable with the experimental rodent studies on caloric deprivation.
Persons and methods
The DOM cohort famine study. The DOM project began in 1974 by F. de Waard to study his hypothesis on the role of overweight on breast and endometrial cancer risk in postmenopausal women as mediated by the nonovarian production of estrogens from adrenal precursors by P450-aromatase in body fat (4). Municipal registration information was used to invite all women in Utrecht between 50 and 70 y old for a breast cancer screening (32). Women volunteered to be measured before mammography, filled out questionnaires, and brought an overnight urine sample to the Preventicon breast cancer screening center. The urine samples have been stored since 1983 at –20°C in a biological sample bank (14). From women who later also volunteered in the Prospect/EPIC study (European Prospective Investigation into Cancer and Nutrition), a blood sample was collected between 1993 and 1997 and was stored at –196°C (33). Additional data have been collected during subsequent screening rounds.
Over time, the interest in the causes of breast cancer in Utrecht shifted toward the lower end of the caloric intake scale and earlier phases in life. Thus in 1983, a prospective study was started among the cohorts born between 1932 and 1942 to study long-term effects of exposure to the Dutch famine of 1944–1945 (18). This study on early life events and their effects on cancer risk was inspired by the work of Susser and Stein (16,17) who had used a crude geographic area classification to assess famine exposure status. Working with breast cancer screening cohorts provided an opportunity to obtain individual exposure data. However, the recruiting scheme of the population-based breast cancer screening of the DOM project did not allow, in 1983, recruitment of women younger than 40 y old. This combined with the fact that by 1986 Xerox mammograms were replaced by Röntgen mammograms resulted pragmatically in a focus on the effects of postnatal exposure to the Dutch famine occurring between 2 and 33 y old.
Another group under Lumey continued Susser and Stein’s work on long-term effects of prenatal, intrauterine famine exposure effects on noncancer chronic disease effects (19). A group under van den Brandt used a cohort of both males and females also included effects of famine from exposure after age 13 y by geographical exposure areas (20). Thus the DOM cohorts are also unique in that they capture a wider range of postnatal ages.
A DOM cohort nested cancer study had to await follow-up until 2000 to be completed (34). During the follow-up period (1983–2000), studies were done to see whether traits that are also breast cancer risk factors, which every woman has, such as height, age at menarche, and body weight, had been affected by the famine. Famine exposure in the DOM cohort was defined by a summary score based on 3 questions about individual recollections of suffering from hunger and cold and having lost weight (35,36). The women had also been asked in which city they lived during the famine. Depending on age at exposure, the percentage of women classified as unexposed varied from 40% to 64%; as moderately exposed, from 33% to 45%; and as severely exposed, from 3% to 15%. Although anchorage effects may have made women underestimate their absolute levels of suffering, the internal comparison used was based on relative ranking and thus should not invalidate the results and at most may have led to underestimation of the famine effect (34–36).
Methods. Descriptive statistics and regression analysis adjusting for covariates were used in the studies reviewed. Statistical analysis was done with SPSS® 10. The age categories chosen to study the effect of famine exposure by developmental stages reflect phases of female development as defined by Bogin (37).
Menarche
The first famine-related study in the DOM cohort was of effects on the menarche. Results indicated that, in a secular trend pattern of declining ages at menarche, a distinct later age at menarche was found for the women exposed to the famine. The largest effect was seen in the cohort born in 1930, which was 14 y old during the famine (35). Age 14 y was the expected age at menarche in The Netherlands. The effects were clearer when exposure classification was based on individual recollections as opposed to classifications based on city or area of residence during the war, which was the exposure measure first used in the study by Stein and Susser (16).
Anthropometry: adult height
A second study addressed height (Table 1) (36,38). In the famine study, we chose to include adult height, sitting height, and arm span measurements to allow for distinguishing possible differential effects on long epiphysial bone growth, which stops after puberty, and enchondral bone growth, as occurs in the lumbar spine, which can show lifelong changes such as the decline with age due to osteoporosis (39).
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Weight, BMI, and waist:hip ratio
Body weight and adult height were measured from the start of the study in the whole cohort, whereas waist and hip measurements for calculating the waist:hip ratio were added in 1985. All women were over 40 y old when measured. Overall, no lasting effects of postnatal famine exposure were detectable on adult body weight, BMI, or waist:hip ratio (Table 1) (36).
Menopause
A substantial number of women, especially those exposed before adulthood, were still premenopausal at the time of the first screening when they filled out the questionnaires on famine exposure. Only after due follow-up in subsequent screening rounds was it possible to determine their ages at menopause. A decrease in the mean age at menopause was found, especially in women who had been exposed to the famine before age 10 y (43), thus reflecting again a shift in a preventive direction. Our previous work indicated that the age at natural menopause has a rather strong heritable component, the fraction variation explained by heritability (h) was h2 = 0.71 – 0.87 (44) and that other factors, such as smoking and body weight, that contribute to the variation in ages at menopause combined account only for 
5–10% of the variance. These factors have their effect late in life, around the expected date of occurrence of menopause (45). Thus, finding an effect of famine exposure that reduced the menopause by 1.83 y; 95% CI: –3.03 to –0.63 was unexpected. This effect so many years after exposure to the famine represents a reduction of 4%, which is comparatively large (43,44,46). The largest reductions in age at menopause were seen when famine exposure had occurred between 2 to 9 y old. Famine exposure thus had shifted all 3 breast cancer risk factors studied so far in the expected, preventive direction.
Mammographic density patterns and dysplasia
Breast cancer screening mammograms were made of all women in the DOM project. These mammograms were also classified by amount of dysplasia (Dy), coded as a proportion of the breast occupied by radio-dense tissue and collapsed to a dichotomous score of yes 50% or more dysplasia, or no Dy (47–49). This allowed us to investigate relationships between famine exposure and its effects on mammographic patterns (50).
Table 2 clearly indicates how famine exposure before age 10 y affects Dy levels later in life. Women exposed before 12 y old had 20% less dysplasia, whereas women exposed after 18 y old had 36% more dysplasia than nonexposed women of the same ages. Famine exposure thus dissociated this risk factor in either a preventive direction of less Dy in women exposed before breast development and increased Dy levels in women exposed after 18 y old when prepregnancy breast growth is complete.
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From mother–daughter and sister pairs participating in the DOM cohort, we estimated the heritability of dysplasia, and, just as we found for menopause, heritability was rather high, explaining 68–88% of the variance in Dy. However, parity can modify the heritable components of dysplasia (52).
As observed before with effects on height, menarche, and menopause, 2 to 9 y old, before puberty and breast development, stand out as a new window of vulnerability for breast cancer risk by caloric deprivation. The effects are most clearly seen in nulliparous women who never experienced a pregnancy, which led us to consider a hypothalamic development mechanism (50).
Urinary postmenopausal hormones
A study using urine samples from a group randomly drawn from the postmenopausal women in the DOM project who were controls in a study on urinary hormone levels and cancer allowed us to explore relationships with their famine exposure status (53). The ages at exposure were limited to 19–32 y, thus rather late in reproductive life. Only data from 163 famine-exposed women who had not used hormone replacement therapy (HRT) or oral contraceptives were available for analysis. To our surprise, we could detect effects of exposure to the famine, but the higher hormone levels found point in a direction more compatible with increases in breast cancer risks (54) (Table 3). As found for menopause and dysplasia, this effect was clearest among women who had not been pregnant (54). After age, years since menopause, smoking at time of donation of urine sample, socioeconomic status, parity, and BMI were controlled for, the results were significant for both estrone and estradiol (54).
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The stronger results for nulliparous women gave a further impulse to our thinking about a hypothalamus-driven regulatory mechanism, especially because others had found that pregnancy can permanently change (lower) the levels of hormone production (55,56). In addition, premenarcheal and menarcheal characteristics also have such long-term effects on hormonal profiles (57,58). In rodents, caloric restriction can permanently shift the levels for mRNAs for gonadotropin synthesis (59).
The postulated set-point hypothesis states that, whereas the levels/set points of gonadotrophin and other trophins may differ among women, the set points themselves may be modified permanently by "exogenous" events, such as caloric restriction and pregnancy. Over time, the net result of these effects depends on the order and the time in a woman’s life when these exogenous events occur. The trophic hormones would thus provide a more proximate link to the risk of cancer than the mediating hormone levels (steroids, IGF-1). From this set-point perspective, it is worthwhile to reflect on the assumption of de Waard’s initial hypothesis that estrogens can no longer be produced after the menopause when the ovaries have stopped inducing menstrual cycles. After menopause, estrogens can only derive from adrenal precursors when converted by P450-aromatase in the fatty tissue of women who are overweight. This conflicts with the increased levels of estrogens found in urine of postmenopausal women who had been exposed early in life to the famine and who did not use HRT or oral contraceptives, while controlling for BMI and years since menopause (54). However, from an individual hypothalamic set-point hypothesis, this may make sense because, the menopause is not only the cessation of ovulations after oocyte depletion and a related decline in estrogen and progesterone production (and which has led to the whole HRT supplementation industry).
The menopause marks especially a time of increased (compensatory) production of gonadotropins (60), most likely at the level of the hypothalamus. Testosterone and androstenedione are still produced in the ovarian remnants although at lower levels. The menopause marks also changes in inhibins, antimüllerian hormone, and iron levels (45). At the subcellular level in the mitochondrial outer membrane, gonadotropins modify the conversion of cholesterol into sex steroids, where a luteinizing hormone regulates the P450 side-chain cleavage enzyme and follicle stimulating hormone, the P450 aromatase, not only in ovarian and fat tissue but also in several other tissues, including the brain/hypothalamus (60). Apart from possible relationship of mitochondria to caloric restriction (61), this molecular pathway may provide, at a cellular level, a link to the postmenopausal production of estrogens (54), as induced by the increases in postmenopausal gonadotropins, also in nonobese women. This concept may also explain our other finding after the menopause reflecting growth and/or trophic hormones operating on the breast. From the 1130 postmenopausal DOM participants 54 to 71 y old who filled out a separate questionnaire, 20% had had to buy a bigger bra after menopause (51), an effect only partially explained by changes in body weight. Hence, these contradictory findings of famine exposure leading to increases in gonadotropin and possibly other tropines (thyroid stimulating hormone, melanocyte stimulating hormone, adrenocorticotrophic hormone, growth hormone, prolactin etc.) seem to fit the above set-point hypothesis. An individual-based set-point hypothesis could also accommodate some rebound effects, such as effects of overfeeding after the war (50) or, for that matter, could explain effects of gonadotropin surges around birth, which again could each be differential within and between women depending on subsequent aspects of development (60).
Plasma IGF-1 and IGFBP-3 levels
Our previous interest in IGF-1, growth hormone, and breast cancer (42) was put in a different perspective given this set-point hypothesis, with growth hormone as another relevant hypothalamic hormone. An opportunity to test this axis occurred because of some overlap between participants in the DOM (14) and the Prospect/EPIC project (33); both studies recruited participants from the ongoing biannual breast cancer project. A random control group of postmenopausal women from the Prospect/EPIC cohort study provided IGF-1 and IGFBP-3 measurements from their blood samples (62,63). Compared with the urinary steroid study, this group was younger, with ages at famine exposure between 2 and 20 y; blood was collected when they were 50 y old and over. The number of women who had also participated in the DOM study was even smaller (n = 87) than in the study on urinary hormone levels (53,54). Again, even with the small number of observations, some significant and long-lasting effects of famine exposure could be detected, fitting the set-point concept (Table 4).
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Breast cancer
With the follow-up extended to January 2000, the number of women who had developed breast cancer as detected by the Integral Kanker Centrum Midden Nederland Cancer Registry was estimated to be large enough to allow the analysis of the case-cohort analysis (34) (Table 5). An increase in breast cancer risk as a result of famine exposure was found. This finding was in contrast with what had been hypothesized at the start of the study based on rodent research and the shifts in menarche, leg length, and menopause but in line with the long-term persistent increases in estrogens and IGF-1 levels. The effects were largest in women who had been exposed to the famine between 2 and 9 y old. The effect among the nulliparous women was twice as high as reflected in a hazard ratio: 2.02; 95% CI: 0.92–4.42, which was larger than that among parous women, hazard ratio: 1.38; 95% CI: 0.99–1.93, so it was larger in women when a full-term pregnancy could not have mitigated the effects of famine exposure (55). Additional univariate analyses indicated that cases and controls were not a selective subset of vulnerable women (Table 6). Instead, famine-exposed women were also slightly shorter and had had a later menarche than unexposed women, thus reflecting effects seen in the whole cohort. Although the early risks indicators, height and menarche, had moved in a preventive direction in cases, this had not affected a final increase in breast cancer risk.
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The central role in the set-point hypothesis for hypothalamic-releasing factors and tropines leads to several predictions that allow testing by other aspects of this set-point hypothesis, both on the specific effects of famine exposure but also of more general differences pertaining to breast cancer levels, such as between populations. Milham (64) already in 1964 pointed to gonadotropin levels and dizygote twinning rates. James (65) predicted that the sex ratio at birth is mediated by shifts in gonadotropins. These related hypotheses thus predict that famine exposure will have increased the number of dizygote births and increased the sex ratio further, causing even more boys to be born. Both these hypotheses fit a more general hypothesis for evolutionary individual survival advantage put forward for animals (66). As to other breast cancer risk factors, we expect that famine exposure may have been affected by the same hypothalamic set-point mechanism—the total number of ovulatory cycles in the reproductive lifespan.
We further predict effects on the incidence of hyperemesis gravidarum in mothers who themselves were exposed to the famine while they were still young girls and on the incidence of their children born left-handed. The mitigating effects of a full-term pregnancy on set points would further predict that effects will be most clearly seen in first but not in later born. This hypothesis also predicts other nongenetic trans-generational effects, such as on birth weight. However, we predict effects also on the unexposed offspring of girls themselves exposed. This then separates maternal- from placental-mediated effects (17) and will be an extension of what has been found for offspring who were exposed intrauterine (19). When peaks or large shifts in gonadotropin levels—either occurring spontaneously or as a rebound phenomenon in relation to caloric restriction—matter, we also predict the existence of effects in male and female newborns who, immediately after birth, developed temporary swellings of their breasts with or without the secretion of so-called witch milk. Even in regular pregnancies with high intrauterine hormone levels, such postnatal swelling of breast tissue may be a marker of a gonadotropin rebound effects (60). In liberated male prisoners of war, such temporary gynecomastia was observed on refeeding (50).
From an even wider perspective this set-point shift concept would fit some old evolutionary well-preserved mechanisms that help to divide energy utilization in times of scarcity between reproduction (investment in the next generation) and maintenance of the maternal organism (investment in the current generation) at least until age 35 y. After age 35 y, reproductive capacities start to decline anyway (67) and other deleterious effects, including the occurrence of reproductive cancers, may start taking their toll (6,7).
Conclusions
The results presented show that famine exposure caused dissociation between effects considered preventive for some early risk factors, while showing an unexpected increase in some hormones and breast cancer risks. The period between ages 2 and 9 y seems a new window of vulnerability with respect to breast cancer risk. Pregnancy may mitigate several cancer-enhancing aspects brought about by a period of about half a year of severe caloric restriction, as occurred during the Dutch famine of 1944–1945.
We think that the dissociation reflects differences in what we would call immediate vs. long-term effects of famine exposure. Changes in hormone secretions by caloric restriction effects on the diencephalic-hypothalamo-pituitary axis at the time of the famine affected height, menarche, and most likely also the oocyte pool with which a woman starts her fertile life. This then would provide a direct link with the earlier menopause observed years later. Starting reproductive life with fewer oocytes or losing more oocytes sooner because of higher or more pulsatile gonadotropin levels might explain why menopause occurred earlier in women exposed to the famine than in women not exposed to the famine. To us this implies that effects of menopause still reflect some early or immediate effects of the famine exposure.
Regarding long-term effects of famine, the famine or the rebound effects after the war may have reset the levels of gonadotropins and possibly other trophic hormones to a higher level or may have increased the pulsatility of secretions (50). Moreover, set-points shifts caused by exposure at an early age might explain why, even after menopause, hormone levels (e.g., estrogen and IGF-1 levels) could still be higher in famine-exposed women. These shifts then might also explain the increases in breast cancer risk and Dy, depending on whether exposure occurred before or after breast development. Increases in breast cancers (5) and comparable regulatory phenomena can be found in animal studies (10–12,59,68).
Because an early first full-term pregnancy is protective for breast cancer, we hypothesize that this is because a pregnancy can also permanently shift gonadotropin levels, though downward, which, in part, could explain a slightly later menopause in women with more children (46) and would explain why famine exposure effects are most clearly seen in nulliparous women. Such hypothalamic set-point phenomena modifiable by individual developmental events provide a more parsimonious hypothesis to summarize many of the previous observations on breast cancer and its risks factors reported in humans. The time dimension that is part of any developmental perspective, including the proposed hypothalamic set-point mechanism, may better cover the range of effects of famine exposure than would a classical epidemiological, often dichotomous, risk-factor perspective that does not consider such a time axis.
This hypothesis also provides an alternative explanation for the increase in breast cancers after menopause observed in Western countries, independent of or at least preceding the effects that would depend on the fat tissue in overweight as suggested by de Waard et al. (14). The aforementioned increases in breast size in 20% of postmenopausal women may also reflect effects on breast cancer target tissue resulting from stimulation by, e.g., high levels of gonadotropins rather than increases in estrogen from adrenal precursor conversion in fat tissue, which mechanistically speaking are also more secondary effects (51).
For future research, the set-point hypothesis leads to numerous testable predictions on differences in a much larger number of hormone levels, such as those between women with an early vs. a late menarche, with and without children, for which others have already provided examples (55,57).
Implications for prevention
The results from these studies do not directly translate into new preventive strategies, although they easily could be misinterpreted to do so. The proposed underlying mechanism points to permanent changes in girls, with implications for their offspring who themselves were not exposed to famine in utero. This adds an extra dimension to our thinking about cancer prevention and who it may affect.
Our results do not detract from the dangers of being overweight but provide a warning that simple severe caloric restriction only for relatively short periods may do more harm than good.
A lifelong lifestyle with a stable, limited amount of calories available for growth (limited by either reduced caloric intake or increased caloric expenditure, such as seen among athletes) might provide a clue to sensible nutritional hygiene. Such a lifestyle most likely is not the current typical Western lifestyle. Large shifts in caloric intake itself, irrespective of duration or direction, may be deleterious and conditional on the age at which they occur. We, however, prefer to interpret such interactions more as effects reflecting a thrifty environment rather than thrifty genes (69), because environmental aspects allow for preventive interventions while genes do not. Essential gaps in our knowledge remain that do not allow for simple evidence-based advice on the potential of rigorous caloric restriction in human cancer prevention. The proposed individual hypothalamic set-point hypothesis may help to formulate a research agenda whereby breast cancer is studied more from a developmental perspective as a disease in which expression is very much under the control of our evolutionary old brain. Both research and prevention may profit when breast cancer is approached as a brain disease.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by World Cancer Research Fund International grant 9996.
4 Abbreviations used: DOM, diagnostic onderzoek mammacarcinoom; Dy, amount of dysplasia; EPIC, European Prospective Investigation into Cancer and Nutrition; HRT, hormone replacement therapy; IGF, insulin-like growth factor; IGFBP-3, IGF binding protein-3.
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LITERATURE CITED |
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