Intrauterine environment, mammary gland mass and breast cancer risk
© BioMed Central Ltd 2003
Received: 23 September 2002
Accepted: 18 October 2002
Published: 4 December 2002
Two intimately linked hypotheses on breast cancer etiology are described. The main postulate of the first hypothesis is that higher levels of pregnancy estrogens and other hormones favor the generation of a higher number of susceptible stem cells with compromised genomic stability. The second hypothesis postulates that the mammary gland mass, as a correlate of the number of cells susceptible to transformation, is an important determinant of breast cancer risk. A simple integrated etiological model for breast cancer is presented and it is indicated that the model accommodates most epidemiological aspects of breast cancer occurrence and natural history.
Keywordsbreast cancer estrogens intrauterine environment mammary gland mass
In the early 1990s, I contributed to the development of two intimately linked hypotheses concerning breast cancer etiology in humans. The first postulated that the intrauterine environment may affect breast cancer risk in the offspring in ways over and beyond those attributed to major breast cancer genes . In the second hypothesis, the argument was made that the number of mammary gland cells, particularly of those among them that are susceptible to transformation, is an important determinant of breast cancer risk . In other words, intrauterine and early life events and conditions could affect the number of mammary gland cells at risk for transformation and, ultimately, breast cancer risk.
Neither of these hypotheses was developed in a vacuum. The earlier work of several authors was instrumental, and indeed critical. The striking protective effect on breast cancer risk of an early first full-term pregnancy led Cole and MacMahon to hypothesize that breast cancer risk is established, in part, early in life . Loeb, as well as other investigators, argued that early phenomena, perhaps affecting mutator genes or other factors controlling genetic stability, are crucial in the process of carcinogenesis . Moolgavkar et al. postulated that the magnitude of breast cancer risk depends on the transition rates of normal susceptible cells to intermediate cells and then to transformed cells . Several authors in the late 1980s suggested that energy intake during early life may affect the number of mammary cells, mammary gland mass and, through them, breast cancer risk .
Intrauterine environment and breast cancer risk
The hypothesis that breast cancer may have intrauterine component causes is based on a number of generally accepted assumptions. Mammary gland cells in utero are not terminally differentiated. Factors that increase the risk of cancer during adult life, as do exogenous and endogenous estrogens for breast cancer, may have similar effects when they act in utero. Estrogens and other hormones with growth enhancing properties are abundant during pregnancy, and adult life exposures do not fully explain the substantial variability of breast cancer occurrence between and within populations.
Simple as it may sound, this hypothesis is very difficult to directly evaluate. The scientific team in Sweden lead by Adami and Ekbom was the first that attempted to evaluate this hypothesis using presumed positive or inverse correlates of pregnancy estrogens, including birth weight and pregnancy toxemia . Pregnancy estrogens have in fact been reported as positively associated with birth weight  and inversely associated with pregnancy toxemia . Several authors have subsequently carried out research along these lines. The results up to 1999 have been reviewed by Potischman and Troisi, who concluded that the collective evidence is consistent with the hypothesis that prenatal exposures, notably pregnancy estrogens, are associated with adult life breast cancer risk . More consistent was the evidence concerning the positive association between birth weight and breast cancer risk in the offspring. Vatten et al. have since reported a positive association from Norway .
It should be noted that a link between perinatal factors and breast cancer risk in the offspring does not necessarily or exclusively incriminate pregnancy estrogens, despite the role of the latter as an important determinant of several of these factors, including birth weight. In addition to pregnancy estrogens , insulin-like growth factor 1 has been positively associated with birth weight  and there is also evidence that alpha fetoprotein may play a role . Nevertheless, among all factors that are associated with birth weight and other perinatal events and conditions linked to breast cancer risk in the offspring, the inherently mammotropic pregnancy estrogens are the most likely candidates, although by no means the only ones . Indeed, a cohort study comparing women exposed in utero to diethylstilbestrol with unexposed women reported a greater than twofold increase in breast cancer risk . This is an ongoing study of a unique cohort, and the women involved have not yet reached the age of high breast cancer incidence. If the results of further followup are in line with those recently reported , it will be difficult to argue against the hypothesis that high in utero estrogenic stimulation increases breast cancer risk in the offspring.
Mammary gland mass and breast cancer risk
With respect to mammary gland mass, as distinct from breast size, the empirical evidence linking it to breast cancer risk is very strong. Mammographic density is a powerful predictor of breast cancer risk and this density is strongly associated with mammary gland mass, although the stromal component is also likely to play an important role [16–19]. Small-breasted women who were motivated to have augmentation mammoplasty, and whose mammary gland mass had to be small, were found to have reduced breast cancer risk [20, 21], although no reduction was evident in a small cohort study that included eight breast cancer cases . Moreover, women who had undergone surgical reduction of their breasts subsequently had reduced breast cancer risk [23–26].
Mammary gland mass, which reflects the total number of mammary cells and can be correlated with mammary cells at risk for transformation, can also explain several of the descriptive aspects of breast cancer epidemiology. One example is breast cancer risk being higher among Caucasian women than among Asian women and being positively associated with adult height [2, 23]. Large breast size mostly reflects adipose tissue but, among thin women, breast size may be a better indicator of mammary gland mass and has been positively associated with breast cancer risk [27, 28].
The number of mammary gland cells at risk for transformation, and thus breast cancer risk, is reduced through the process of terminal differentiation that takes place mostly after the occurrence of the first full-term pregnancy and, to some extent, after the occurrence of subsequent pregnancies and lactation [23, 29, 30]. Moreover, cells at risk or at intermediate stages of transformation may be more or less responsive to the growth enhancing influences of estrogens and other mammotropic hormones, depending on the density of the respective receptors in the nonmalignant tissue. In this context, it may be of relevance that expression of estrogen receptors α has been found to be less common among Japanese women than among Caucasian women .
We have tried to integrate the existing information on breast cancer epidemiology and apparent pathogenesis into an etiological model that incorporates the two presented hypotheses and the data that support them . The model has four components. First, the likelihood of breast cancer occurrence depends on the number of cells at risk and, second, the number of target cells is partially determined early in life, probably even in utero. The third component is that, while a pregnancy stimulates the replication of already initiated cells, it conveys long-term protection through structural changes, including terminal cellular differentiation. Finally, in adult life, mammotropic hormones, in conjunction with their receptors, affect the likelihood of retention of spontaneous somatic mutations and the rate of expansion of initiated clones.
This composite, yet simple, model accommodates most, if not all, epidemiological aspects of breast cancer occurrence and natural history. These include the secular increase of breast cancer incidence during the early part of last century, the higher risk for this disease among higher socioeconomic class women in most countries of the world, as well as the gradual increase of breast cancer incidence among Asian migrants to Western countries. All these patterns reflect concomitant changes in birth size, adult birth height and breast cancer risk. The model also accommodates the effectiveness of prophylactic mastectomy among women at very high risk on the basis of reduction of mammary gland mass [23, 32].
It is too early for passing judgment on the validity of the hypotheses considered in this commentary, but it is not too early to express my gratitude to all the colleagues in Sweden, the USA, Greece and Australia with whom we have worked on these hypotheses over the last 15 years. I am particularly grateful to Prof. Adami and Prof. Ekbom for their continuous insight, input and support throughout these years.
- Trichopoulos D: Hypothesis: does breast cancer originate in utero?. Lancet. 1990, 335: 939-940. 10.1016/0140-6736(90)91000-Z.View ArticlePubMedGoogle Scholar
- Trichopoulos D, Lipman R: Mammary gland mass and breast cancer risk. Epidemiology. 1992, 3: 523-526.View ArticlePubMedGoogle Scholar
- Cole P, MacMahon B: Oestrogen fractions during early reproductive life in the aetiology of breast cancer. Lancet. 1969, 1: 604-606. 10.1016/S0140-6736(69)91537-2.View ArticlePubMedGoogle Scholar
- Loeb LA: Mutator phenotype may be required for multistage carcinogenesis. Cancer Res. 1991, 51: 3075-3079.PubMedGoogle Scholar
- Moolgavkar SH, Day NE, Stevens RG: Two-stage model for carcinogenesis: epidemiology of breast cancer in females. J Natl Cancer Inst. 1980, 65: 559-569.PubMedGoogle Scholar
- DeWaard F, Trichopoulos D: A unifying concept of the aetiology of breast cancer. Int J Cancer. 1988, 41: 666-669.View ArticleGoogle Scholar
- Ekbom A, Trichopoulos D, Adami H-O, Hsieh C-C, Lan S-J: Evidence of prenatal influences on breast cancer risk. Lancet. 1992, 340: 1015-1018. 10.1016/0140-6736(92)93019-J.View ArticlePubMedGoogle Scholar
- Kaijser M, Granath F, Jacobsen G, Cnattingius S, Ekbom A: Maternal pregnancy estriol levels in relation to anamnestic and fetal anthropometric data. Epidemiology. 2000, 11: 315-319. 10.1097/00001648-200005000-00015.View ArticlePubMedGoogle Scholar
- Innes KE, Byers TE: Preeclampsia and breast cancer risk. Epidemiology. 1999, 10: 722-732.View ArticlePubMedGoogle Scholar
- Potischman N, Troisi R: In-utero and early life exposures in relation to risk of breast cancer. Cancer Causes Control. 1999, 10: 561-573. 10.1023/A:1008955110868.View ArticlePubMedGoogle Scholar
- Vatten LJ, Maehle BO, Lund Nilsen TI, Tretli S, Hsieh C-C, Trichopoulos D, Stuver SO: Birth weight as a predictor of breast cancer: a case–control study in Norway. Br J Cancer. 2002, 86: 89-91. 10.1038/sj.bjc.6600011.View ArticlePubMedPubMed CentralGoogle Scholar
- Vatten LJ, Nilsen ST, Odegard RA, Romundstad PR, Austgulen R: Insulin-like growth factor I and leptin in umbilical cord plasma and infant birth size at term. Pediatrics. 2002, 109: 1131-1135.View ArticlePubMedGoogle Scholar
- Vatten LJ, Romundstad PR, Odegard RA, Nilsen ST, Trichopoulos D, Austgulen R: Alpha-foetoprotein in umbilical cord in relation to severe pre-eclampsia, birth weight and future breast cancer risk. Br J Cancer. 2002, 86: 728-731. 10.1038/sj.bjc.6600125.View ArticlePubMedPubMed CentralGoogle Scholar
- Schernhammer ES: In-utero exposures and breast cancer risk: joint effect of estrogens and insulin-like growth factor?. Cancer Causes Control. 2002, 13: 505-508. 10.1023/A:1016348425833.View ArticlePubMedGoogle Scholar
- Palmer JR, Hatch EE, Rosenberg CL, Hartge P, Kaufman RH, Titus-Ernstoff L, Noller KL, Herbst AL, Rao RS, Troisi R, Colton T, Hoover RN: Risk of breast cancer in women exposed to diethylstilbestrol in utero: preliminary results (United States). Cancer Causes Control. 2002, 13: 753-758. 10.1023/A:1020254711222.View ArticlePubMedGoogle Scholar
- Byrne C, Schairer C, Wolfe J, Parekh N, Salane M, Brinton LA, Hoover R, Haile R: Mammographic features and breast cancer risk: effects with time, age, and menopause status. J Natl Cancer Inst. 1995, 87: 1622-1629.View ArticlePubMedGoogle Scholar
- Boyd NF, Lockwood GA, Byng JW, Tritchler DL, Yaffe MJ: Mammographic densities and breast cancer risk. Cancer Epidemiol Biomarkers Prev. 1998, 7: 1133-1144.PubMedGoogle Scholar
- Byrne C, Colditz GA, Willett WC, Speizer FE, Pollak M, Hankinson SE: Plasma insulin-like growth factor (IGF) I, IGF-binding protein 3, and mammographic density. Cancer Res. 2000, 60: 3744-3748.PubMedGoogle Scholar
- Byrne C, Schairer C, Brinton LA, Wolfe J, Parekh N, Salane M, Carter C, Hoover R: Effects of mammographic density and benign breast disease on breast cancer risk (United States). Cancer Causes Control. 2001, 12: 103-110. 10.1023/A:1008935821885.View ArticlePubMedGoogle Scholar
- Berkel H, Birdsell DC, Jenkins H: Breast augmentation: a risk factor for breast cancer?. N Engl J Med. 1992, 326: 1649-1653.View ArticlePubMedGoogle Scholar
- Brinton LA, Lubin JH, Burich MC, Colton T, Brown SL, Hoover RN: Breast cancer following augmentation mammoplasty (United States). Cancer Causes Control. 2000, 11: 819-827. 10.1023/A:1008941110816.View ArticlePubMedGoogle Scholar
- Friis S, McLaughlin JK, Mellemkjaer L, Kjoller KH, Blot WJ, Boice JD, Fraumeni JF, Olsen JH: Breast implants and cancer risk in Denmark. Int J Cancer. 1997, 71: 956-958. 10.1002/(SICI)1097-0215(19970611)71:6<956::AID-IJC8>3.0.CO;2-X.View ArticlePubMedGoogle Scholar
- Adami H-O, Signorello LB, Trichopoulos D: Towards an understanding of breast cancer etiology. Semin Cancer Biol. 1998, 8: 255-262. 10.1006/scbi.1998.0077.View ArticlePubMedGoogle Scholar
- Brown MH, Weinberg M, Chong N, Levine R, Holowaty E: A cohort study of breast cancer risk in breast reduction patients. Plast Reconstr Surg. 1999, 103: 1674-1681. 10.1097/00006534-199905060-00015.View ArticlePubMedGoogle Scholar
- Boice JD, Persson I, Brinton LA, Hober M, McLaughlin JK, Blot WJ, Fraumeni JF, Nyren O: Breast cancer following breast reduction surgery in Sweden. Plast Reconstr Surg. 2000, 106: 755-762. 10.1097/00006534-200009040-00001.View ArticlePubMedGoogle Scholar
- Brinton LA, Persson I, Boice JD, McLaughlin JK, Fraumeni JF: Breast cancer risk in relation to amount of tissue removed during breast reduction operations in Sweden. Cancer. 2001, 91: 478-483. 10.1002/1097-0142(20010201)91:3<478::AID-CNCR1025>3.0.CO;2-5.View ArticlePubMedGoogle Scholar
- Swanson CA, Coates RJ, Schoenberg JB, Malone KE, Gammon MD, Stanford JL, Shorr IJ, Potischman NA, Brinton LA: Body size and breast cancer risk among women under age 45 years. Am J Epidemiol. 1996, 143: 698-706.View ArticlePubMedGoogle Scholar
- Egan KM, Newcomb PA, Titus-Ernstoff L, Trentham-Dietz A, Baron JA, Willett WC, Stampfer MJ, Trichopoulos D: The relation of breast size to breast cancer risk in postmenopausal women (United States). Cancer Causes Control. 1999, 10: 115-118. 10.1023/A:1008801131831.View ArticlePubMedGoogle Scholar
- Russo J, Romero AI, Russo IH: Architectural pattern of the normal and cancerous breast under the influence of parity. Cancer Epidemiol Biomark Prev. 1994, 3: 219-224.Google Scholar
- Sivaraman L, Medina D: Hormone-induced protection against breast cancer. J Mammary Gland Biol Neoplasia. 2002, 7: 77-92. 10.1023/A:1015774524076.View ArticlePubMedGoogle Scholar
- Lawson JS, Field AS, Champion S, Tran D, Ishikura H, Trichopoulos D: Low estrogen receptor a expression in normal breast tissue underlies low breast cancer incidence in Japan. Lancet. 1999, 354: 1787-1788. 10.1016/S0140-6736(99)04936-3.View ArticlePubMedGoogle Scholar
- Schrag D, Kuntz KM, Garber JE, Weeks JC: Life expectancy gains from cancer prevention strategies for women with breast cancer and BRCA1 or BRCA2 mutations. JAMA. 2000, 283: 617-624. 10.1001/jama.283.5.617.View ArticlePubMedGoogle Scholar