Advertisement

Exposures to Synthetic Estrogens at Different Times During the Life, and Their Effect on Breast Cancer Risk

  • Leena Hilakivi-Clarke
  • Sonia de Assis
  • Anni Warri
Article

Abstract

Women are using estrogens for many purposes, such as to prevent pregnancy or miscarriage, or to treat menopausal symptoms. Estrogens also have been used to treat breast cancer which seems puzzling, since there is convincing evidence to support a link between high lifetime estrogen exposure and increased breast cancer risk. In this review, we discuss the findings that maternal exposure to the synthetic estrogen diethylstilbestrol during pregnancy increases breast cancer risk in both exposed mothers and their daughters. In addition, we review data regarding the use of estrogens in oral contraceptives and as postmenopausal hormone therapy and discuss the opposing effects on breast cancer risk based upon timing of exposure. We place particular emphasis on studies investigating how maternal estrogenic exposures during pregnancy increase breast cancer risk among daughters. New data suggest that these exposures induce epigenetic modifications in the mammary gland and germ cells, thereby causing an inheritable increase in breast cancer risk for multiple generations.

Keywords

Synthetic estrogens Pregnancy In utero Oral contraceptives Hormone therapy Epigenetics 

Abbreviations

BIRADS

breast imaging reporting and data system

BMP4

bone morphogenic protein 4

CCA

clear cell adenocarcinoma

CEE

conjugated equine estrogens

DES

diethylstilbestrol

DMBA

9,12-dimethylbenz[a]anthracene

DNMT

DNA methyltransferase

E2

17-β estradiol

EE2

ethinyl estradiol

EPIC

european prospective investigation into cancer and nutrition

ERα

estrogen receptor α

ERβ

estrogen receptor β

EZH2

enhancer of zeste-2

FGF

fibroblast growth factors

HF

high fat

HDAC

histone deacetylase

HT

hormone therapy

hESC

human embryonic stem cells

IGF

insulin-like growth factor

MNU

methylnitrosourea

NSABP

national surgical adjuvant breast and bowel project

MPA

medroxyprogesterone acetate

miRNA

microRNAs

OC

oral contraceptives

PTHrP

parathyroid hormone-related protein

PTH1R

parathyroid hormone 1 receptor

PcTG

polycomb target genes

P

progesterone

RPFNA

random periareolar fine-needle aspiration

STAR

study of tamoxifen and raloxifene

TAM

tamoxifen

TDLU

terminal ductal lobular unit

TEB

terminal end buds

TSG

tumor suppressor gene

WHI

women’s health initiative

Notes

Disclosure

L. Hilakivi-Clarke has served as an expert witness in a case concerning breast cancer risk in daughters of DES-exposed mothers on behalf of the plaintiffs

Funding support

This study was supported by the National Cancer Institute (R01 CA164384-01A1, U54 CA100970, U54CA149147, and P30 CA051668)

References

  1. 1.
    Burns KA, Korach KS. Estrogen receptors and human disease: an update. Arch Toxicol. 2012;86:1491–504.PubMedCrossRefGoogle Scholar
  2. 2.
    Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest. 2006;116:561–70.PubMedCrossRefGoogle Scholar
  3. 3.
    Lovejoy JC. The menopause and obesity. Prim Care. 2003;30:317–25.PubMedCrossRefGoogle Scholar
  4. 4.
    Davis SR, Castelo-Branco C, Chedraui P, et al. Understanding weight gain at menopause. Climacteric. 2012;15:419–29.PubMedCrossRefGoogle Scholar
  5. 5.
    Rossouw JE, Anderson GL, Prentice RL, 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;288:321–33.PubMedCrossRefGoogle Scholar
  6. 6.
    Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s health initiative randomized controlled trial. JAMA. 2004;291:1701–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Samaras K, Hayward CS, Sullivan D, Kelly RP, Campbell LV. Effects of postmenopausal hormone replacement therapy on central abdominal fat, glycemic control, lipid metabolism, and vascular factors in type 2 diabetes: a prospective study. Diabetes Care. 1999;22:1401–7.PubMedCrossRefGoogle Scholar
  8. 8.
    American Cancer Society. Breast cancer: facts and figures 2011–2012. Atlanta: American Cancer Society; 2012.Google Scholar
  9. 9.
    Henderson BE, Ross R, Bernstein L. Estrogens as a cause of human cancer. Cancer Res. 1988;48:246–53.PubMedGoogle Scholar
  10. 10.
    Vogel VG. The NSABP Study of Tamoxifen and Raloxifene (STAR) trial. Expert Rev Anticancer Ther. 2009;9:51–60.PubMedCrossRefGoogle Scholar
  11. 11.
    Sestak I, Cuzick J. Preventive Therapy for Breast Cancer. Curr Oncol Rep. 2012;14:568–73.Google Scholar
  12. 12.
    Guzman RC, Yang J, Rajkumar L, Thordarson G, Chen X, Nandi S. Hormonal prevention of breast cancer: mimicking the protective effect of pregnancy. Proc Natl Acad Sci USA. 1999;96:2520–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Ariazi EA, Cunliffe HE, Lewis-Wambi JS, et al. Estrogen induces apoptosis in estrogen deprivation-resistant breast cancer through stress responses as identified by global gene expression across time. Proc Natl Acad Sci U S A. 2011;108:18879–86.PubMedCrossRefGoogle Scholar
  14. 14.
    Clarke R, Dickson RB, Lippman ME. Hormonal aspects of breast cancer. Growth factors, drugs and stromal interactions. Crit Rev Oncol Hematol. 1992;12:1–23.PubMedCrossRefGoogle Scholar
  15. 15.
    Hilakivi-Clarke L, Onojafe I, Raygada M, Cho E, Clarke R, Lippman M. Breast cancer risk in rats fed a diet high in n-6 polyunsaturated fatty acids during pregnancy. J Natl Cancer Inst. 1996;88:1821–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Hilakivi-Clarke L, Clarke R, Onojafe I, Raygada M, Cho E, Lippman ME. A maternal diet high in n-6 polyunsaturated fats alters mammary gland development, puberty onset, and breast cancer risk among female rat offspring. Proc Natl Acad Sci USA. 1997;94:9372–7.PubMedCrossRefGoogle Scholar
  17. 17.
    de Assis S, Warri A, Cruz MI, et al. High-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring. Nat Commun. 2012;3:1053.PubMedCrossRefGoogle Scholar
  18. 18.
    Bernstein L, Ross RK. Endogenous hormones and breast cancer risk. Epidemiological Reviews. 1993;15:48–65.Google Scholar
  19. 19.
    Cleary MP, Grossmann ME. Minireview: obesity and breast cancer: the estrogen connection. Endocrinology. 2009;150:2537–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Cecchini RS, Costantino JP, Cauley JA, et al. Body mass index and the risk for developing invasive breast cancer among high-risk women in NSABP P-1 and STAR breast cancer prevention trials. Cancer Prev Res (Phila). 2012;4:583–92.CrossRefGoogle Scholar
  21. 21.
    Ritte R, Lukanova A, Tjonneland A et al. Height, age at menarche and risk of hormone receptor positive and negative breast cancer: A cohort study. Int J Cancer 2012.Google Scholar
  22. 22.
    The Collaborative Group on Hormonal Factors in Breast Cancer. Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13:1141–51.Google Scholar
  23. 23.
    Olsson H, Landin-Olsson M, Gullberg B. Retrospective assessment of menstrual cycle length in patients with breast cancer, in patients with benign breast disease, and in women without breast disease. J Natl Cancer Inst. 1983;70:17–20.PubMedGoogle Scholar
  24. 24.
    Kelsey JL, Gammon MD, John EM. Reproductive factors and breast cancer. Epidemiol Rev. 1993;15:36–47.PubMedGoogle Scholar
  25. 25.
    Whelan EA, Sandler DP, Root JL, Smith KR, Weinberg CR. Menstrual cycle patterns and risk of breast cancer. Am J Epidemiol. 1994;140:1081–90.PubMedGoogle Scholar
  26. 26.
    Terry KL, Willett WC, Rich-Edwards JW, Hunter DJ, Michels KB. Menstrual cycle characteristics and incidence of premenopausal breast cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:1509–13.PubMedCrossRefGoogle Scholar
  27. 27.
    Butler LM, Potischman NA, Newman B, et al. Menstrual risk factors and early-onset breast cancer. Cancer Causes Control. 2000;11:451–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Orgeas CC, Hall P, Rosenberg LU, Czene K. The influence of menstrual risk factors on tumor characteristics and survival in postmenopausal breast cancer. Breast Cancer Res. 2008;10:R107.PubMedCrossRefGoogle Scholar
  29. 29.
    Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95:1218–26.PubMedCrossRefGoogle Scholar
  30. 30.
    Diorio C, Lemieux J, Provencher L, Hogue JC, Vachon E. Aromatase inhibitors in obese breast cancer patients are not associated with increased plasma Estradiol levels. Breast Cancer Res Treat. 2012;136:573–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Dorgan JF, Reichman ME, Judd JT, et al. The relation of body size to plasma levels of estrogens and androgens in premenopausal women (Maryland, United States). Cancer Causes Control. 1995;6:3–8.PubMedCrossRefGoogle Scholar
  32. 32.
    van den Brandt PA, Spiegelman D, Yaun SS, et al. Pooled analysis of prospective cohort studies on height, weight, and breast cancer risk. Am J Epidemiol. 2000;152:514–27.PubMedCrossRefGoogle Scholar
  33. 33.
    Lahmann PH, Lissner L, Gullberg B, Olsson H, Berglund G. A prospective study of adiposity and postmenopausal breast cancer risk: the Malmo diet and cancer study. Int J Cancer. 2003;103:246–52.PubMedCrossRefGoogle Scholar
  34. 34.
    Lahmann PH, Hoffmann K, Allen N, et al. Body size and breast cancer risk: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer. 2004;111:762–71.PubMedCrossRefGoogle Scholar
  35. 35.
    Li CI, Malone KE, Daling JR. Interactions between body mass index and hormone therapy and postmenopausal breast cancer risk (United States). Cancer Causes Control. 2006;17:695–703.PubMedCrossRefGoogle Scholar
  36. 36.
    Modugno F, Kip KE, Cochrane B, et al. Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer. Int J Cancer. 2006;118:1292–301.PubMedCrossRefGoogle Scholar
  37. 37.
    Poehlman ET, Toth MJ, Gardner AW. Changes in energy balance and body composition at menopause: a controlled longitudinal study. Ann Intern Med. 1995;123:673–5.PubMedGoogle Scholar
  38. 38.
    Vona-Davis L, Howard-McNatt M, Rose DP. Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer. Obes Rev. 2007;8:395–408.PubMedCrossRefGoogle Scholar
  39. 39.
    Boyd NF, Martin LJ, Stone J, Greenberg C, Minkin S, Yaffe MJ. Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention. Curr Oncol Rep. 2001;3:314–21.PubMedCrossRefGoogle Scholar
  40. 40.
    Boyd NF, Martin LJ, Yaffe MJ, Minkin S. Mammographic density and breast cancer risk: current understanding and future prospects. Breast Cancer Res. 2011;13:223.PubMedCrossRefGoogle Scholar
  41. 41.
    Kerlikowske K, Cook AJ, Buist DS, et al. Breast cancer risk by breast density, menopause, and postmenopausal hormone therapy use. J Clin Oncol. 2010;28:3830–7.PubMedCrossRefGoogle Scholar
  42. 42.
    Becker S, Kaaks R. Exogenous and endogenous hormones, mammographic density and breast cancer risk: can mammographic density be considered an intermediate marker of risk? Recent Results Cancer Res. 2009;181:135–57.PubMedCrossRefGoogle Scholar
  43. 43.
    Martin LJ, Minkin S, Boyd NF. Hormone therapy, mammographic density, and breast cancer risk. Maturitas. 2009;64:20–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Cuzick J, Warwick J, Pinney E, et al. Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: a nested case–control study. J Natl Cancer Inst. 2011;103:744–52.PubMedCrossRefGoogle Scholar
  45. 45.
    Decensi A, Robertson C, Guerrieri-Gonzaga A, et al. Randomized double-blind 2 × 2 trial of low-dose tamoxifen and fenretinide for breast cancer prevention in high-risk premenopausal women. J Clin Oncol. 2009;27:3749–56.PubMedCrossRefGoogle Scholar
  46. 46.
    Pearman L, Kagan R, Arsenault J, Muram D. The effects of raloxifene on mammographic breast density: a review of clinical trials. Menopause. 2010;17:654–9.PubMedGoogle Scholar
  47. 47.
    Huggins C, Moon RC, Morii S. Extinction of experimental mammary cancer.I. Estradiol-17beta and progesterone. Proc Natl Acad Sci USA. 1962;48:379–86.PubMedCrossRefGoogle Scholar
  48. 48.
    Cabanes A, Wang M, Olivo S, et al. Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis. Carcinogenesis. 2004;25:741–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Grubbs CJ, Peckham JC, McDonough KD. Effect of ovarian hormones on the induction of l-methyl-l-nitrosurea-induced mammary cancer. Carcinogenesis. 1983;4:495–7.PubMedCrossRefGoogle Scholar
  50. 50.
    LaCroix AZ, Chlebowski RT, Manson JE, et al. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA. 2011;305:1305–14.PubMedCrossRefGoogle Scholar
  51. 51.
    Nelson HD, Walker M, Zakher B, Mitchell J. Menopausal hormone therapy for the primary prevention of chronic conditions: a systematic review to update the U.S. Preventive services task force recommendations. Ann Intern Med. 2012;157:104–13.PubMedGoogle Scholar
  52. 52.
    Bernstein L. Epidemiology of endocrine-related risk factors for breast cancer. J Mammary Gland Biol Neoplasia. 2002;7:3–15.PubMedCrossRefGoogle Scholar
  53. 53.
    Grubbs CJ, Farneli DR, Hill DL, McDonough KC. Chemoprevention of n-nitro-n-methylurea-induced mammary cancers by pretreatment with 17beta-estradiol and progesterone. J Natl Cancer Inst. 1985;74:927–31.PubMedGoogle Scholar
  54. 54.
    Sivaraman L, Stephens LC, Markaverich BM, et al. Hormone-induced refractoriness to mammary carcinogenesis in wistar-furth rats. Carcinogenesis. 1998;19:1573–81.PubMedCrossRefGoogle Scholar
  55. 55.
    Rajkumar L, Guzman RC, Yang J, Thordarson G, Talamantes F, Nandi S. Short-term exposure to pregnancy levels of estrogen prevents mammary carcinogenesis. Proc Natl Acad Sci U S A. 2001;98:11755–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Britt K, Ashworth A, Smalley M. Pregnancy and the risk of breast cancer. Endocr Relat Cancer. 2007;14:907–33.PubMedCrossRefGoogle Scholar
  57. 57.
    Russo IH, Russo J. Pregnancy-induced changes in breast cancer risk. J Mammary Gland Biol Neoplasia. 2011;16:221–33.PubMedCrossRefGoogle Scholar
  58. 58.
    Siwko SK, Dong J, Lewis MT, Liu H, Hilsenbeck SG, Li Y. Evidence that an early pregnancy causes a persistent decrease in the number of functional mammary epithelial stem cells–implications for pregnancy-induced protection against breast cancer. Stem Cells. 2008;26:3205–9.PubMedCrossRefGoogle Scholar
  59. 59.
    D'Cruz CM, Moody SE, Master SR, et al. Persistent parity-induced changes in growth factors, TGF-beta3, and differentiation in the rodent mammary gland. Mol Endocrinol. 2002;16:2034–51.PubMedCrossRefGoogle Scholar
  60. 60.
    Blakely CM, Stoddard AJ, Belka GK, et al. Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy. Cancer Res. 2006;66:6421–31.PubMedCrossRefGoogle Scholar
  61. 61.
    Belitskaya-Levy I, Zeleniuch-Jacquotte A, Russo J, et al. Characterization of a genomic signature of pregnancy identified in the breast. Cancer Prev Res (Phila). 2011;4:1457–64.CrossRefGoogle Scholar
  62. 62.
    Twombly R. Estrogen’s dual nature? studies highlight effects on breast cancer. J Natl Cancer Inst. 2011;103:920–1.PubMedCrossRefGoogle Scholar
  63. 63.
    Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365:1687–717.Google Scholar
  64. 64.
    Mahtani RL, Stein A, Vogel CL. High-dose estrogen as salvage hormonal therapy for highly refractory metastatic breast cancer: a retrospective chart review. Clin Ther. 2009;31(Pt 2):2371–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Ellis MJ, Gao F, Dehdashti F, et al. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA. 2009;302:774–80.PubMedCrossRefGoogle Scholar
  66. 66.
    Dieckmann WJ, Davis ME, Rynkiewitz LM, Pottinger RE. Does the administration of diethylstilbestrol during pregnancy have therapeutic value? Am J Obstet Gynecol. 1953;66:1062–81.PubMedGoogle Scholar
  67. 67.
    Hoover RN, Hyer M, Pfeiffer RM, et al. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med. 2011;365:1304–14.PubMedCrossRefGoogle Scholar
  68. 68.
    Physicians desk reference to pharmaceutical specialties and biologicals, 15th Edition, 1961: 625.Google Scholar
  69. 69.
    Herbst AL, Ulfelder H, Poskanzer DC. Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med. 1971;284:878–81.PubMedCrossRefGoogle Scholar
  70. 70.
    Palmer JR, Wise LA, Hatch EE, et al. Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 2006;15:1509–14.PubMedCrossRefGoogle Scholar
  71. 71.
    Troisi R, Hatch EE, Titus-Ernstoff L, et al. Cancer risk in women prenatally exposed to diethylstilbestrol. Int J Cancer. 2007;121:356–60.PubMedCrossRefGoogle Scholar
  72. 72.
    Colton T, Greenberg R, Noller K, et al. Breast cancer in mothers prescribed diethylstilbestrol in pregnancy. JAMA. 1993;269:2096–100.PubMedCrossRefGoogle Scholar
  73. 73.
    Hatch EE, Palmer JR, Titus-Ernstoff L, et al. Cancer risk in women exposed to diethylstilbestrol in utero. JAMA. 1998;280:630–4.PubMedCrossRefGoogle Scholar
  74. 74.
    Palmer JR, Hatch EE, Rosenberg CL, et al. Risk of breast cancer in women exposed to diethylstilbestrol in utero: preliminary results (United States). Cancer Causes Control. 2002;13:753–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Verloop J, van Leeuwen FE, Helmerhorst TJ, van Boven HH, Rookus MA. Cancer risk in DES daughters. Cancer Causes Control. 2010;21:999–1007.PubMedCrossRefGoogle Scholar
  76. 76.
    Boylan ES, Calhoon RE. Mammary tumorigenesis in the rat following prenatal exposure to diethylstilbestrol and postnatal treatment with 7,12-dimethylbenz[a]anthracene. J Toxicol Environ Health. 1979;5:1059–71.PubMedCrossRefGoogle Scholar
  77. 77.
    Boylan ES, Calhoon RE. Prenatal exposure to diethylstilbestrol: ovarian-independent growth of mammary tumors induced by 7,12-dimethylbenz[a]anthracene. J Natl Cancer Inst. 1981;66:649–52.PubMedGoogle Scholar
  78. 78.
    Boylan ES, Calhoon RE. Transplacental action of diethylstilbestrol on mammary carcinogenesis in female rats given one or two doses of 7,12-dimethylbenz(a)anthracene. Cancer Res. 1983;43:4879–84.PubMedGoogle Scholar
  79. 79.
    Rothschild TC, Boylan ES, Calhoon RE, Vonderhaar BK. Transplacental effects of diethylstilbestrol on mammary development and tumorigenesis in female ACI rats. Cancer Res. 1987;47:4508–16.PubMedGoogle Scholar
  80. 80.
    Vassilacopoulou D, Boylan ES. Mammary gland morphology and responsiveness to regulatory molecules following prenatal exposure to diethylstilbestrol. Teratog Carcinog Mutagen. 1993;13:59–74.PubMedCrossRefGoogle Scholar
  81. 81.
    Kawaguchi H, Miyoshi N, Miyamoto Y, et al. Effects of exposure period and dose of diethylstilbestrol on pregnancy in rats. J Vet Med Sci. 2009;71:1309–15.PubMedCrossRefGoogle Scholar
  82. 82.
    Ninomiya K, Kawaguchi H, Souda M, et al. Effects of neonatally administered diethylstilbestrol on induction of mammary carcinomas induced by 7, 12-dimethylbenz(a)anthracene in female rats. Toxicol Pathol. 2007;35:813–8.PubMedCrossRefGoogle Scholar
  83. 83.
    Stark AH, Kossoy G, Zusman I, Yarden G, Madar Z. Olive oil consumption during pregnancy and lactation in rats influences mammary cancer development in female offspring. Nutr Cancer. 2003;46:59–65.PubMedCrossRefGoogle Scholar
  84. 84.
    Walker BE. Tumors in female offspring of control and diethylstilbestrol-exposed mice fed high-fat diets. J Nat Cancer Inst. 1990;82:50–4.PubMedCrossRefGoogle Scholar
  85. 85.
    Luijten M, Thomsen AR, van den Berg JA, et al. Effects of soy-derived isoflavones and a high-fat diet on spontaneous mammary tumor development in Tg.NK (MMTV/c-neu) mice. Nutr Cancer. 2004;50:46–54.PubMedCrossRefGoogle Scholar
  86. 86.
    Raun AP, Preston RL. History of diethystilbestrol use in cattle. American Society of Animal Science 2001;1–7.Google Scholar
  87. 87.
    Preston RL, Byers F, Stevens KR. Estrogenic activity and growth stimulation in steers fed varying protein levels. J Anim Sci. 1978;46:541–6.PubMedGoogle Scholar
  88. 88.
    Sakakura T. Mammary embryogenesis. In: Neville MC, Daniel CW, editors. Mammary gland: development, regulation, and function. New York: Plenum Press; 1987. p. 37.Google Scholar
  89. 89.
    Robinson GW, Karpf AB, Kratochwil K. Regulation of mammary gland development by tissue interaction. J Mammary Gland Biol Neoplasia. 1999;4:9–19.PubMedCrossRefGoogle Scholar
  90. 90.
    Cowin P, Wysolmerski J. Molecular mechanisms guiding embryonic mammary gland development. Cold Spring Harb Perspect Biol. 2010;2:a003251.PubMedCrossRefGoogle Scholar
  91. 91.
    Hens JR, Wysolmerski JJ. Key stages of mammary gland development: molecular mechanisms involved in the formation of the embryonic mammary gland. Breast Cancer Res. 2005;7:220–4.PubMedCrossRefGoogle Scholar
  92. 92.
    Vandenberg LN, Maffini MV, Wadia PR, Sonnenschein C, Rubin BS, Soto AM. Exposure to environmentally relevant doses of the xenoestrogen bisphenol-a alters development of the fetal mouse mammary gland. Endocrinology. 2007;148:116–27.PubMedCrossRefGoogle Scholar
  93. 93.
    Keeling JW, Ozer E, King G, Walker F. Oestrogen receptor alpha in female fetal, infant, and child mammary tissue. J Pathol. 2000;191:449–51.PubMedCrossRefGoogle Scholar
  94. 94.
    Naccarato AG, Viacava P, Vignati S, et al. Bio-morphological events in the development of the human female mammary gland from fetal age to puberty. Virchows Arch. 2000;436:431–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Bocchinfuso WP, Lindzey JK, Hewitt SC, et al. Induction of mammary gland development in estrogen receptor-alpha knockout mice. Endocrinology. 2000;141:2982–94.PubMedCrossRefGoogle Scholar
  96. 96.
    Sinkevicius KW, Burdette JE, Woloszyn K, et al. An estrogen receptor-alpha knock-in mutation provides evidence of ligand-independent signaling and allows modulation of ligand-induced pathways in vivo. Endocrinology. 2008;149:2970–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Vrettos AS, Fotiou S, Papaharalampus N. Development of the breasts of the fetus. Effects of the administration of hormonal preparations during pregnancy. J Gynecol Obstet Biol Reprod (Paris). 1976;5:561–6.Google Scholar
  98. 98.
    Tomooka Y, Bern HA. Growth of mouse mammary glands after neonatal sex hormone treatment. J Natl Cancer Inst. 1982;69:1347–52.PubMedGoogle Scholar
  99. 99.
    Varea O, Garrido JJ, Dopazo A, Mendez P, Garcia-Segura LM, Wandosell F. Estradiol activates beta-catenin dependent transcription in neurons. PLoS One. 2009;4:e5153.PubMedCrossRefGoogle Scholar
  100. 100.
    Zhang L, Kharbanda S, Hanfelt J, Kern FG. Both autocrine and paracrine effects of transfected acidic fibroblast growth factor are involved in the estrogen-independent and antiestrogen-resistant growth of MCF-7 breast cancer cells. Cancer Res. 1998;58:352–61.PubMedGoogle Scholar
  101. 101.
    Nallasamy S, Li Q, Bagchi MK, Bagchi IC. Msx homeobox genes critically regulate embryo implantation by controlling paracrine signaling between uterine stroma and epithelium. PLoS Genet. 2012;8:e1002500.PubMedCrossRefGoogle Scholar
  102. 102.
    Fagan DH, Yee D. Crosstalk between IGF1R and estrogen receptor signaling in breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:423–9.PubMedCrossRefGoogle Scholar
  103. 103.
    Fillmore CM, Gupta PB, Rudnick JA, et al. Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci U S A. 2010;107:21737–42.PubMedCrossRefGoogle Scholar
  104. 104.
    Rabbani SA, Khalili P, Arakelian A, Pizzi H, Chen G, Goltzman D. Regulation of parathyroid hormone-related peptide by estradiol: effect on tumor growth and metastasis in vitro and in vivo. Endocrinology. 2005;146:2885–94.PubMedCrossRefGoogle Scholar
  105. 105.
    Funk JL, Wei H. Regulation of parathyroid hormone-related protein expression in MCF-7 breast carcinoma cells by estrogen and antiestrogens. Biochem Biophys Res Commun. 1998;251:849–54.PubMedCrossRefGoogle Scholar
  106. 106.
    Kajitani T, Tamamori-Adachi M, Okinaga H, Chikamori M, Iizuka M, Okazaki T. Negative regulation of parathyroid hormone-related protein expression by steroid hormones. Biochem Biophys Res Commun. 2011;407:472–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Giacomini D, Paez-Pereda M, Stalla J, Stalla GK, Arzt E. Molecular interaction of BMP-4, TGF-beta, and estrogens in lactotrophs: impact on the PRL promoter. Mol Endocrinol. 2009;23:1102–14.PubMedCrossRefGoogle Scholar
  108. 108.
    Hilakivi-Clarke LA, Raygada M, Stoica A, Martin M-B. Consumption of a high-fat diet during pregnancy alters estrogen receptor content, protein kinase C activity and morphology of mammary gland in the mother and her female offspring. Cancer Res. 1998;58:654–60.PubMedGoogle Scholar
  109. 109.
    Cabanes A, de Assis S, Gustafsson JA, Hilakivi-Clarke L. Maternal high n-6 polyunsaturated fatty acid intake during pregnancy increases voluntary alcohol intake and hypothalamic estrogen receptor alpha and beta levels among female offspring. Dev Neurosci. 2000;22:488–93.PubMedCrossRefGoogle Scholar
  110. 110.
    Bern HA, Edery M, Mills KT, Kohrman AF, Mori T, Larson L. Long-term alterations in histology and steroid receptor levels of the genital tract and mammary gland following neonatal exposure of female BALB/cCrgl mice to various doses of diethylstilbestrol. Cancer Res. 1987;47:4165–72.PubMedGoogle Scholar
  111. 111.
    Shajahan A, Goel S, de Assis S, Yu B, Clarke R, Hilakivi-Clarke L. Changes in mammary caveolin-1 signaling pathways are associated with breast cancer risk in rats exposed to estradiol in utero or during prepuberty. Hormone Molecular Biology and Clinical Investigation. 2010;2:227–34.CrossRefGoogle Scholar
  112. 112.
    Hilakivi-Clarke L. Cabanes A, de AS et al. In utero alcohol exposure increases mammary tumorigenesis in rats Br J Cancer. 2004;90:2225–31.Google Scholar
  113. 113.
    Hovey RC. sai-Sato M, Warri A et al. Effects of neonatal exposure to diethylstilbestrol, tamoxifen, and toremifene on the BALB/c mouse mammary gland. Biol Reprod. 2005;72:423–35.PubMedCrossRefGoogle Scholar
  114. 114.
    Jones LA, Bern HA. Long-term effects of neonatal treatment with progesterone, alone and in combination with estrogen, on the mammary gland and reproductive tract of female BALB/cfC3H mice. Cancer Res. 1977;37:67–75.PubMedGoogle Scholar
  115. 115.
    Mori T, Nagasawa H, Bern HA. Long-term effects of perinatal exposure to hormones on normal and neoplastic mammary growth in rodents: a review. J Environ Pathol Toxicol. 1979;3:191–205.PubMedGoogle Scholar
  116. 116.
    Hilakivi-Clarke L. Nutritional modulation of terminal end buds: its relevance to breast cancer prevention. Curr Cancer Drug Targets. 2007;7:465–74.PubMedCrossRefGoogle Scholar
  117. 117.
    Russo J, Russo IH. Biological and molecular bases of mammary carcinogenesis. Lab Investig. 1987;57:112–37.PubMedGoogle Scholar
  118. 118.
    Russo J, Hu YF, Yang X, Russo IH. Developmental, cellular, and molecular basis of human breast cancer. J Natl Cancer Inst Monogr 2000;17–37.Google Scholar
  119. 119.
    Russo J, Russo IH. Influence of differentiation and cell kinetics on the susceptibility of the rat mammary gland to carcinogenesis. Cancer Res. 1980;40:2677–87.PubMedGoogle Scholar
  120. 120.
    Telang NT, Suto A, Wong GY, Osborne MP, Bradlow HL. Induction by estrogen metabolite 16 alpha-hydroxyestrone of genotoxic damage and aberrant proliferation in mouse mammary epithelial cells. J Natl Cancer Inst. 1992;84:634–8.PubMedCrossRefGoogle Scholar
  121. 121.
    Umekita Y, Souda M, Hatanaka K, et al. Gene expression profile of terminal end buds in rat mammary glands exposed to diethylstilbestrol in neonatal period. Toxicol Lett. 2011;205:15–25.PubMedCrossRefGoogle Scholar
  122. 122.
    Zhang B, Tian Y, Jin L, et al. DDN: a caBIG(R) analytical tool for differential network analysis. Bioinformatics. 2011;27:1036–8.PubMedCrossRefGoogle Scholar
  123. 123.
    Connelly L, Barham W, Onishko HM, et al. Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burden. Oncogene. 2011;30:1402–12.PubMedCrossRefGoogle Scholar
  124. 124.
    Biswas DK, Shi Q, Baily S, et al. NF-kappa B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci U S A. 2004;101:10137–42.PubMedCrossRefGoogle Scholar
  125. 125.
    Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet Jr RJ, Sledge Jr GW. Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth. Mol Cell Biol. 1997;17:3629–39.PubMedGoogle Scholar
  126. 126.
    Santos F, Dean W. Epigenetic reprogramming during early development in mammals. Reproduction. 2004;127:643–51.PubMedCrossRefGoogle Scholar
  127. 127.
    Sato K, Fukata H, Kogo Y, Ohgane J, Shiota K, Mori C. Neonatal exposure to diethylstilbestrol alters expression of DNA methyltransferases and methylation of genomic DNA in the mouse uterus. Endocr J. 2009;56:131–9.PubMedCrossRefGoogle Scholar
  128. 128.
    Sato K, Fukata H, Kogo Y, Ohgane J, Shiota K, Mori C. Neonatal exposure to diethylstilbestrol alters the expression of DNA methyltransferases and methylation of genomic DNA in the epididymis of mice. Endocr J. 2006;53:331–7.PubMedCrossRefGoogle Scholar
  129. 129.
    Rhee I, Bachman KE, Park BH, et al. DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature. 2002;416:552–6.PubMedCrossRefGoogle Scholar
  130. 130.
    Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28:1057–68.PubMedCrossRefGoogle Scholar
  131. 131.
    Biniszkiewicz D, Gribnau J, Ramsahoye B, et al. Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality. Mol Cell Biol. 2002;22:2124–35.PubMedCrossRefGoogle Scholar
  132. 132.
    Ting AH, McGarvey KM, Baylin SB. The cancer epigenome–components and functional correlates. Genes Dev. 2006;20:3215–31.PubMedCrossRefGoogle Scholar
  133. 133.
    Cooney CA, Dave AA, Wolff GL. Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr. 2002;132:2393S–400S.PubMedGoogle Scholar
  134. 134.
    Tang WY, Newbold R, Mardilovich K et al. Persistent hypomethylation in the promoter of nucleosomal binding protein 1 (Nsbp1) correlates with overexpression of Nsbp1 in mouse uteri neonatally exposed to diethylstilbestrol or genistein. Endocrinology 2008;149:5922–31.Google Scholar
  135. 135.
    Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect. 2006;114:567–72.PubMedCrossRefGoogle Scholar
  136. 136.
    Ho SM, Tang WY. Belmonte dF, Prins GS. Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res. 2006;66:5624–32.PubMedCrossRefGoogle Scholar
  137. 137.
    Block K, Kardana A, Igarashi P, Taylor HS. In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing mullerian system. FASEB J. 2000;14:1101–8.PubMedGoogle Scholar
  138. 138.
    Bromer JG, Wu J, Zhou Y, Taylor HS. Hypermethylation of homeobox A10 by in utero diethylstilbestrol exposure: an epigenetic mechanism for altered developmental programming. Endocrinology. 2009;150:3376–82.PubMedCrossRefGoogle Scholar
  139. 139.
    Li S, Hansman R, Newbold R, Davis B, McLachlan JA, Barrett JC. Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol Carcinog. 2003;38:78–84.PubMedCrossRefGoogle Scholar
  140. 140.
    Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128:635–8.PubMedCrossRefGoogle Scholar
  141. 141.
    Kouzarides T. Chromatin modifications and their function. Cell. 2007;128:693–705.PubMedCrossRefGoogle Scholar
  142. 142.
    Jenuwein T, Allis CD. Translating the histone code. Science. 2001;293:1074–80.PubMedCrossRefGoogle Scholar
  143. 143.
    Li H, Fischle W, Wang W, et al. Structural basis for lower lysine methylation state-specific readout by MBT repeats of L3MBTL1 and an engineered PHD finger. Mol Cell. 2007;28:677–91.PubMedCrossRefGoogle Scholar
  144. 144.
    Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev. 2006;20:1123–36.PubMedCrossRefGoogle Scholar
  145. 145.
    Herranz N, Pasini D, Diaz VM, et al. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol. 2008;28:4772–81.PubMedCrossRefGoogle Scholar
  146. 146.
    Doherty LF, Bromer JG, Zhou Y, Aldad TS, Taylor HS. In utero exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) increases EZH2 expression in the mammary gland: an epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer 2010; 15 May.Google Scholar
  147. 147.
    Lee TI, Jenner RG, Boyer LA, et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006;125:301–13.PubMedCrossRefGoogle Scholar
  148. 148.
    Meissner A, Mikkelsen TS, Gu H, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature. 2008;454:766–70.PubMedGoogle Scholar
  149. 149.
    Vasilatos SN, Broadwater G, Barry WT, et al. CpG island tumor suppressor promoter methylation in non-BRCA-associated early mammary carcinogenesis. Cancer Epidemiol Biomarkers Prev. 2009;18:901–14.PubMedCrossRefGoogle Scholar
  150. 150.
    Easwaran H, Johnstone SE, Van NL, et al. A DNA hypermethylation module for the stem/progenitor cell signature of cancer. Genome Res. 2012;22:837–49.PubMedCrossRefGoogle Scholar
  151. 151.
    Gao J, Wang J, Wang Y, Dai W, Lu L. Regulation of Pax6 by CTCF during induction of mouse ES cell differentiation. PLoS One. 2011;6:e20954.PubMedCrossRefGoogle Scholar
  152. 152.
    Mohn F, Weber M, Rebhan M, et al. Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors. Mol Cell. 2008;30:755–66.PubMedCrossRefGoogle Scholar
  153. 153.
    Cheng AS, Culhane AC, Chan MW, et al. Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome. Cancer Res. 2008;68:1786–96.PubMedCrossRefGoogle Scholar
  154. 154.
    Moelans CB, Verschuur-Maes AH, van Diest PJ. Frequent promoter hypermethylation of BRCA2, CDH13, MSH6, PAX5, PAX6 and WT1 in ductal carcinoma in situ and invasive breast cancer. J Pathol. 2011;225:222–31.PubMedCrossRefGoogle Scholar
  155. 155.
    Jiang Y, Tong D, Lou G, Zhang Y, Geng J. Expression of RUNX3 gene, methylation status and clinicopathological significance in breast cancer and breast cancer cell lines. Pathobiology. 2008;75:244–51.PubMedCrossRefGoogle Scholar
  156. 156.
    Park SY, Kwon HJ, Lee HE, et al. Promoter CpG island hypermethylation during breast cancer progression. Virchows Arch. 2011;458:73–84.PubMedCrossRefGoogle Scholar
  157. 157.
    Suter MA, Chen A, Burdine MS et al. A maternal high-fat diet modulates fetal SIRT1 histone and protein deacetylase activity in nonhuman primates. FASEB J. 2012;26:5106-14.Google Scholar
  158. 158.
    Yang KF, Cai W, Xu JL, Shi W. Maternal high-fat diet programs Wnt genes through histone modification in the liver of neonatal rats. J Mol Endocrinol. 2012;49:107–14.PubMedGoogle Scholar
  159. 159.
    Zheng S, Li Q, Zhang Y, Balluff Z, Pan YX. Histone deacetylase 3 (HDAC3) participates in the transcriptional repression of the p16 (INK4a) gene in mammary gland of the female rat offspring exposed to an early-life high-fat diet. Epigenetics. 2012;7:183–90.PubMedCrossRefGoogle Scholar
  160. 160.
    Bredfeldt TG, Greathouse KL, Safe SH, Hung MC, Bedford MT, Walker CL. Xenoestrogen-induced regulation of EZH2 and histone methylation via estrogen receptor signaling to PI3K/AKT. Mol Endocrinol. 2010;24:993–1006.PubMedCrossRefGoogle Scholar
  161. 161.
    Jackson RJ, Standart N. How do microRNAs regulate gene expression? Sci.STKE. 2007; 2007:re1.Google Scholar
  162. 162.
    Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Kerin MJ. MicroRNAs as Novel Biomarkers for Breast Cancer. J Oncol. 2009;2009:950201.PubMedGoogle Scholar
  163. 163.
    Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 2005;120:15–20.PubMedCrossRefGoogle Scholar
  164. 164.
    Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 2009;19:92–105.PubMedCrossRefGoogle Scholar
  165. 165.
    Maillot G, Lacroix-Triki M, Pierredon S, et al. Widespread estrogen-dependent repression of micrornas involved in breast tumor cell growth. Cancer Res. 2009;69:8332–40.PubMedCrossRefGoogle Scholar
  166. 166.
    Heneghan HM, Miller N, Lowery AJ, Sweeney KJ, Newell J, Kerin MJ. Circulating microRNAs as novel minimally invasive biomarkers for breast cancer. Ann Surg. 2010;251:499–505.PubMedCrossRefGoogle Scholar
  167. 167.
    Yamagata K, Fujiyama S, Ito S, et al. Maturation of microRNA is hormonally regulated by a nuclear receptor. Mol Cell. 2009;36:340–7.PubMedCrossRefGoogle Scholar
  168. 168.
    Cheng C, Fu X, Alves P, Gerstein M. mRNA expression profiles show differential regulatory effects of microRNAs between estrogen receptor-positive and estrogen receptor-negative breast cancer. Genome Biol. 2009;10:R90.PubMedCrossRefGoogle Scholar
  169. 169.
    Adams BD, Claffey KB, White BA. Argonaute-2 expression is regulated by epidermal growth factor receptor and mitogen-activated protein kinase signaling and correlates with a transformed phenotype in breast cancer cells. Endocrinology. 2009;150:14–23.PubMedCrossRefGoogle Scholar
  170. 170.
    Hilakivi-Clarke, L., de Assis, S., Clarke, R., Warri, A., Marian, C., Zwart, A., Jin, L., Kim, D. J., Tian, Y., Zhang, B., Wang, Y., and Xuan, J. Elevated in utero estrogenic environment may increase later breast cancer risk by down-regulating miRNAs. American Association for Cancer Research 102. 2011.Google Scholar
  171. 171.
    Weber B, Stresemann C, Brueckner B, Lyko F. Methylation of human microRNA genes in normal and neoplastic cells. Cell Cycle. 2007;6:1001–5.PubMedCrossRefGoogle Scholar
  172. 172.
    Neves R, Scheel C, Weinhold S, et al. Role of DNA methylation in miR-200c/141 cluster silencing in invasive breast cancer cells. BMC Res Notes. 2010;3:219.PubMedCrossRefGoogle Scholar
  173. 173.
    Lujambio A, Calin GA, Villanueva A, et al. A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci U S A. 2008;105:13556–61.PubMedCrossRefGoogle Scholar
  174. 174.
    Cao Q, Mani RS, Ateeq B, et al. Coordinated regulation of polycomb group complexes through microRNAs in cancer. Cancer Cell. 2011;20:187–99.PubMedCrossRefGoogle Scholar
  175. 175.
    Zheng F, Liao YJ, Cai MY, et al. The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2. Gut. 2012;61:278–89.PubMedCrossRefGoogle Scholar
  176. 176.
    Wellner U, Schubert J, Burk UC, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 2009;11:1487–95.PubMedCrossRefGoogle Scholar
  177. 177.
    Rijnkels M, Kabotyanski E, Montazer-Torbati MB, et al. The epigenetic landscape of mammary gland development and functional differentiation. J Mammary Gland Biol Neoplasia. 2010;15:85–100.PubMedCrossRefGoogle Scholar
  178. 178.
    Huang TH, Esteller M. Chromatin remodeling in mammary gland differentiation and breast tumorigenesis. Cold Spring Harb Perspect Biol. 2010;2:a004515.PubMedCrossRefGoogle Scholar
  179. 179.
    Schuettengruber B, Cavalli G. Recruitment of polycomb group complexes and their role in the dynamic regulation of cell fate choice. Development. 2009;136:3531–42.PubMedCrossRefGoogle Scholar
  180. 180.
    Maruyama R, Choudhury S, Kowalczyk A, et al. Epigenetic regulation of cell type-specific expression patterns in the human mammary epithelium. PLoS Genet. 2011;7:e1001369.PubMedCrossRefGoogle Scholar
  181. 181.
    Lee HJ, Hinshelwood RA, Bouras T, et al. Lineage specific methylation of the Elf5 promoter in mammary epithelial cells. Stem Cells. 2011;29:1611–9.PubMedCrossRefGoogle Scholar
  182. 182.
    Cao H, Yang CS, Rana TM. Evolutionary emergence of microRNAs in human embryonic stem cells. PLoS One. 2008;3:e2820.PubMedCrossRefGoogle Scholar
  183. 183.
    Gunaratne PH. Embryonic stem cell microRNAs: defining factors in induced pluripotent (iPS) and cancer (CSC) stem cells? Curr Stem Cell Res Ther. 2009;4:168–77.PubMedCrossRefGoogle Scholar
  184. 184.
    Avril-Sassen S, Goldstein LD, Stingl J, et al. Characterisation of microRNA expression in post-natal mouse mammary gland development. BMC Genomics. 2009;10:548.PubMedCrossRefGoogle Scholar
  185. 185.
    Greene SB, Gunaratne PH, Hammond SM, Rosen JM. A putative role for microRNA-205 in mammary epithelial cell progenitors. J Cell Sci. 2010;123:606–18.PubMedCrossRefGoogle Scholar
  186. 186.
    Savarese TM, Strohsnitter WC, Low HP, et al. Correlation of umbilical cord blood hormones and growth factors with stem cell potential: implications for the prenatal origin of breast cancer hypothesis. Breast Cancer Res. 2007;9:R29.PubMedCrossRefGoogle Scholar
  187. 187.
    Lukanova A, Surcel HM, Lundin E, et al. Circulating estrogens and progesterone during primiparous pregnancies and risk of maternal breast cancer. Int J Cancer. 2012;130:910–20.PubMedCrossRefGoogle Scholar
  188. 188.
    Peck JD, Hulka BS, Poole C, Savitz DA, Baird D, Richardson BE. Steroid hormone levels during pregnancy and incidence of maternal breast cancer. Cancer Epidemiol Biomarkers Prev. 2002;11:361–8.PubMedGoogle Scholar
  189. 189.
    Enger SM, Ross RK, Henderson B, Bernstein L. Breastfeeding history, pregnancy experience and risk of breast cancer. Br J Cancer. 1997;76:118–23.PubMedCrossRefGoogle Scholar
  190. 190.
    Wohlfahrt J, Melbye M. Maternal risk of breast cancer and birth characteristics of offspring by time since birth. Edidemiology. 1999;10:441–4.CrossRefGoogle Scholar
  191. 191.
    Depue RH, Bernstein L, Ross RK, Judd HL, Henderson BE. Hyperemesis gravidarum in relation to estradiol levels, pregnancy outcome, amd other maternal factors: a seroepidemiologic study. Am J Obstet Gynecol. 1987;156:1137–41.PubMedGoogle Scholar
  192. 192.
    Nagata C, Iwasa S, Shiraki M, Shimizu H. Estrogen and alpha-fetoprotein levels in maternal and umbilical cord blood samples in relation to birth weight. Cancer Epidemiol Biomarkers Prev. 2006;15:1469–72.PubMedCrossRefGoogle Scholar
  193. 193.
    Asztalos S, Gann PH, Hayes MK, et al. Gene expression patterns in the human breast after pregnancy. Cancer Prev Res (Phila). 2010;3:301–11.CrossRefGoogle Scholar
  194. 194.
    Russo J, Rivera R, Russo IH. Influence of age and parity on the development of the human breast. Breast Cancer Res Treat. 1992;23:211–8.PubMedCrossRefGoogle Scholar
  195. 195.
    Hilakivi-Clarke L, de Assis S, Warri A, Luoto R. Pregnancy hormonal environment and mother’s breast cancer risk. Horm Mol Biol Clin Investig. 2012;9:11–23.CrossRefGoogle Scholar
  196. 196.
    Britt KL, Kendrick H, Regan JL, et al. Pregnancy in the mature adult mouse does not alter the proportion of mammary epithelial stem/progenitor cells. Breast Cancer Res. 2009;11:R20.PubMedCrossRefGoogle Scholar
  197. 197.
    Tiede BJ, Owens LA, Li F, DeCoste C, Kang Y. A novel mouse model for non-invasive single marker tracking of mammary stem cells in vivo reveals stem cell dynamics throughout pregnancy. PLoS One. 2009;4:e8035.PubMedCrossRefGoogle Scholar
  198. 198.
    Bronson RA. Oral contraception: mechanism of action. Clin Obstet Gynecol. 1981;24:869–77.PubMedCrossRefGoogle Scholar
  199. 199.
    Mishell Jr DR. State of the art in hormonal contraception: an overview. Am J Obstet Gynecol. 2004;190:S1–4.PubMedCrossRefGoogle Scholar
  200. 200.
    Gaspard UJ, Romus MA, Gillain D, Duvivier J, Mey-Ponsart E, Franchimont P. Plasma hormone levels in women receiving new oral contraceptives containing ethinyl estradiol plus levonorgestrel or desogestrel. Contraception. 1983;27:577–90.PubMedCrossRefGoogle Scholar
  201. 201.
    Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996;347:1713–27.CrossRefGoogle Scholar
  202. 202.
    Burkman R, Schlesselman JJ, Zieman M. Safety concerns and health benefits associated with oral contraception. Am J Obstet Gynecol. 2004;190:S5–S22.PubMedCrossRefGoogle Scholar
  203. 203.
    Kumle M, Weiderpass E, Braaten T, Persson I, Adami HO, Lund E. Use of oral contraceptives and breast cancer risk: The Norwegian-Swedish Women’s Lifestyle and Health Cohort Study. Cancer Epidemiol Biomarkers Prev. 2002;11:1375–81.PubMedGoogle Scholar
  204. 204.
    Hunter DJ, Colditz GA, Hankinson SE, et al. Oral contraceptive use and breast cancer: a prospective study of young women. Cancer Epidemiol Biomarkers Prev. 2010;19:2496–502.PubMedCrossRefGoogle Scholar
  205. 205.
    Nelson HD, Zakher B, Cantor A, et al. Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med. 2012;156:635–48.PubMedGoogle Scholar
  206. 206.
    Marchbanks PA, Curtis KM, Mandel MG, et al. Oral contraceptive formulation and risk of breast cancer. Contraception. 2012;85:342–50.PubMedCrossRefGoogle Scholar
  207. 207.
    Greendale GA, Reboussin BA, Hogan P, et al. Symptom relief and side effects of postmenopausal hormones: results from the Postmenopausal Estrogen/Progestin Interventions Trial. Obstet Gynecol. 1998;92:982–8.PubMedCrossRefGoogle Scholar
  208. 208.
    Barrett-Connor E, Grady D. Hormone replacement therapy, heart disease, and other considerations. Annu Rev Public Health. 1998;19:55–72.PubMedCrossRefGoogle Scholar
  209. 209.
    Bain C, Willett W, Hennekens CH, Rosner B, Belanger C, Speizer FE. Use of postmenopausal hormones and risk of myocardial infarction. Circulation. 1981;64:42–6.PubMedCrossRefGoogle Scholar
  210. 210.
    The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA. 1995;273:199–208.CrossRefGoogle Scholar
  211. 211.
    Heiss G, Wallace R, Anderson GL, et al. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA. 2008;299:1036–45.PubMedCrossRefGoogle Scholar
  212. 212.
    Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–13.PubMedCrossRefGoogle Scholar
  213. 213.
    Lacey Jr JV, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA. 2002;288:334–41.PubMedCrossRefGoogle Scholar
  214. 214.
    Hernan MA, Alonso A, Logan R, et al. Observational studies analyzed like randomized experiments: an application to postmenopausal hormone therapy and coronary heart disease. Edidemiology. 2008;19:766–79.CrossRefGoogle Scholar
  215. 215.
    Cheek J, Lacy J, Toth-Fejel S, Morris K, Calhoun K, Pommier RF. The impact of hormone replacement therapy on the detection and stage of breast cancer. Arch Surg. 2002;137:1015–9.PubMedCrossRefGoogle Scholar
  216. 216.
    Holli K, Isola J, Cuzick J. Low biologic aggressiveness in breast cancer in women using hormone replacement therapy. J Clin Oncol. 1998;16:3115–20.PubMedGoogle Scholar
  217. 217.
    Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295:1647–57.PubMedCrossRefGoogle Scholar
  218. 218.
    Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA. 2004;291:47–53.PubMedCrossRefGoogle Scholar
  219. 219.
    Ravdin PM, Cronin KA, Howlader N, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007;356:1670–4.PubMedCrossRefGoogle Scholar
  220. 220.
    Chlebowski RT, Anderson G, Pettinger M, et al. Estrogen plus progestin and breast cancer detection by means of mammography and breast biopsy. Arch Intern Med. 2008;168:370–7.PubMedCrossRefGoogle Scholar
  221. 221.
    Gierach GL, Ichikawa L, Kerlikowske K, et al. Relationship between mammographic density and breast cancer death in the Breast Cancer Surveillance Consortium. J Natl Cancer Inst. 2012;104:1218–27.PubMedCrossRefGoogle Scholar
  222. 222.
    Davey DA. Update: estrogen and estrogen plus progestin therapy in the care of women at and after the menopause. Womens Health (Lond Engl). 2012;8:169–89.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Leena Hilakivi-Clarke
    • 1
    • 3
  • Sonia de Assis
    • 1
  • Anni Warri
    • 1
    • 2
  1. 1.Department of OncologyGeorgetown UniversityWashingtonUSA
  2. 2.Institute of BiomedicineUniversity of Turku Medical FacultyTurkuFinland
  3. 3.Georgetown University Medical CenterWashingtonUSA

Personalised recommendations