Pregnancy-Induced Changes in Breast Cancer Risk

  • Irma H. Russo
  • Jose Russo


Breast cancer is the malignant disease most frequently diagnosed in women of all races and nationalities. Since the 1970s the worldwide incidence of this disease has increased 30–40% in postmenopausal women, in whom, paradoxically, the risk of developing breast cancer is significantly reduced by an early first full term pregnancy (FTP) as compared to nulliparous and late parous women. Although the cause of breast cancer is not known, the mechanisms mediating the protection conferred by an early FTP have been identified to reside in the breast itself, and to be modulated by endogenous and environmental exposures that might negatively affect this organ during specific windows in its development that extend from prenatal life until the first pregnancy. Soon after conception the embryo initiates the production of human chorionic gonadotropin (hCG), the glycoprotein hormone that is diagnostic of pregnancy. HCG in conjunction with ovarian steroid hormones primes the hypothalamic neuroendocrine system for maintaining the pregnancy. Higher levels of hCG during the first trimester of pregnancy have been associated with a reduction in maternal breast cancer incidence after age 50. In preclinical studies it has been demonstrated that both FTP and hCG treatment of virgin rats prevent the development of chemically-induced mammary tumors, a phenomenon mediated by the differentiation of the mammary gland epithelial cells prior to carcinogen exposure. Complete differentiation proceeds through complex morphological, physiological and molecular changes that occur during pregnancy and lactation, that ultimately result in increased DNA repair capabilities of the mammary epithelium, activation of genes controlling differentiation and programmed cell death and imprinting in the breast epithelium a specific and permanent genomic signature of pregnancy. This signature is indicative of a reduced breast cancer risk and serves as a molecular biomarker of differentiation for evaluating the potential use of chemopreventive agents.


Breast cancer prevention Early pregnancy Human chorionic gonadotropin Late pregnancy Breast cancer risk Hypothalamic aging Hypothalamic–pituitary–gonadal axis 



alveolar bud




estrogen receptor


full term pregnancy


Genetically engineered mice


gonadotropin releasing hormone


Gene Ontology


human chorionic gonadotropin


human growth hormone


hypothalamic–pituitary–gonadal axis


human placental lactogen


hormonal prevention window


high risk susceptibility window


intermediate cell


interleukin 1beta-converting enzyme


intraductal proliferation


luteinizing hormone




mammary cancer stem cell


monthly fecundity rate


polycyclic aromatic hydrocarbons


preoptic area


progenitor mammary stem cells


progesterone receptor




rat chorionic gonadotropin


rat placental lactogen


terminal end buds


testosterone repressed prostate message 2


  1. 1.
    Breasted JH, editor. The Edwin Smith Surgical Papyrus: published in facsimile and hieroglyphic transliteration with translation and commentary in two volumes, vol. 1. Chicago: University of Chicago Press; 1991.Google Scholar
  2. 2.
    Clarke CA, Purdie DM, Glaser SL. Population attributable risk of breast cancer in white women associated with immediately modifiable risk factors. BMC Cancer. 2006;6:170.PubMedCrossRefGoogle Scholar
  3. 3.
    Botha JL, Bray F, Sanlika R, Parkin DM. Breast cancer incidence and mortality trends in 16 European countries. Europ J Cancer. 2003;39:1718–29.CrossRefGoogle Scholar
  4. 4.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Nagata C, Mizoue T, Tanaka K, Tsuji I, Wakai K, Inoue M, et al. Tobacco smoking and breast cancer risk: an evaluation based on a systematic review of epidemiological evidence among the Japanese population. Jpn J Clin Oncol. 2006;36:387–94.PubMedCrossRefGoogle Scholar
  6. 6.
    Maskarinec G, Pagano I, Chen Z, Nagata C, Gram IT. Ethnic and geographic differences in mammographic density and their association with breast cancer incidence. Breast Cancer Res Treat. 2007;104:47–56.PubMedCrossRefGoogle Scholar
  7. 7.
    Althuis MD, Dozier JM, Anderson WF, Devesa SS, Brinton LA. Global trends in breast cancer incidence and mortality 1973–1997. Int J Epidemiol. 2005;34:405–12.PubMedCrossRefGoogle Scholar
  8. 8.
    MacMahon B, Cole P, Lin TM, Lowe CR, Mirra AP, Ravnihar B, et al. Age at first birth and breast cancer risk. Bull World Health Organ. 1970;43:209–21.PubMedGoogle Scholar
  9. 9.
    Hinkula M, Pukkala E, Kyyrönen P, Kauppila A. Grand multiparity and the risk of breast cancer: population-based study in Finland. Cancer Causes Control. 2001;12:491–500.PubMedCrossRefGoogle Scholar
  10. 10.
    Ma H, Henderson KD, Sullivan-Halley J, Duan L, Marshall SF, Ursin G, et al. Pregnancy-related factors and the risk of breast carcinoma in situ and invasive breast cancer among postmenopausal women in the California Teachers Study cohort. Breast Cancer Res. 2010;12:R35.PubMedCrossRefGoogle Scholar
  11. 11.
    Phipps AI, Chlebowski RT, Prentice R, McTiernan A, Wactawski-Wende J, Kuller LH, et al. Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. J Natl Cancer Inst. 2011;103:1–8.CrossRefGoogle Scholar
  12. 12.
    Toniolo P, Grankvist K, Wulff M, Chen T, Johansson R, Schock H, et al. Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer. Cancer Res. 2010;70:6779–86.PubMedCrossRefGoogle Scholar
  13. 13.
    Mustacchi P. Ramazzini and Rigoni-Stern on parity and breast cancer. Clinical impression and statistical corroboration. Arch Intern Med. 1961;108:639–42.PubMedGoogle Scholar
  14. 14.
    Kroman N, Mouridsen HT. Prognostic influence of pregnancy before, around, and after diagnosis of breast cancer. Breast. 2003;12:516–21.PubMedCrossRefGoogle Scholar
  15. 15.
    Kroman N, Melbye M, Mouridsen HT. Prognostic influence of age at diagnosis in premenopausal breast cancer patients. Scand J Surg. 2002;91:305–8.PubMedGoogle Scholar
  16. 16.
    Brinton LA, Sherman ME, Carreon JD, Anderson WF. Recent trends in breast cancer among younger women in the United States. J Natl Cancer Inst. 2008;100:1643–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Downs JL, Wise PM. The role of the brain in female reproductive aging. Mol Cell Endocrinol. 2009;299:32–8.PubMedCrossRefGoogle Scholar
  18. 18.
    Russo IH, Medado J, Russo J. Endocrine influences on mammary gland structure and development. In: Jones TC, Mohr U, Hunt RD, editors. Integument and mammary gland of laboratory animals. Berlin: Springer Verlag; 1989. p. 252–66.Google Scholar
  19. 19.
    Chen T, Lundin E, Grankvist K, Zeleniuch-Jacquotte A, Wulff M, Afanasyeva Y, et al. Maternal hormones during early pregnancy: a cross-sectional study. Cancer Causes Control. 2010;21:719–27.PubMedCrossRefGoogle Scholar
  20. 20.
    Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases. Lancet. 1896;2:104.CrossRefGoogle Scholar
  21. 21.
    Russo J, Russo IH. The role of estrogen in the initiation of breast cancer. Steroid Biochem Mol Biol. 2006;102:89–96.CrossRefGoogle Scholar
  22. 22.
    Russo J, Russo IH, editors. Molecular basis of breast cancer: prevention and treatment. Berlin: Springer Verlag; 2004.Google Scholar
  23. 23.
    Lukanova A, Surcel HM, Lundin E, Kaasila M, Lakso HA, Schock H, et al. Circulating estrogens and progesterone during primiparous. pregnancies and risk of maternal breast cancer. Int J Cancer 2011; March16: 000:000–000.Google Scholar
  24. 24.
    Albrektsen G, Heuch I, Thoresen S, Kvale G. Clinical stage of breast cancer by parity, age at birth, and time since birth: a progressive effect of pregnancy hormones? Cancer Epidemiol Biomarkers Prev. 2006;15:65–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Russo IH, Koszalka M, Gimotty PA, Russo J. Protective effect of chorionic gonadotropin on DMBA-induced mammary carcinogenesis. Br J Cancer. 1990;62:243–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Russo IH, Koszalka M, Russo J. Comparative study of the influence of pregnancy and hormonal treatment on mammary carcinogenesis. Br J Cancer. 1991;64:481–4.PubMedCrossRefGoogle Scholar
  27. 27.
    Russo J, Russo IH. Susceptibility of the mammary gland to carcinogenesis. II. Pregnancy interruption as a risk factor in tumor incidence. Am J Pathol. 1980;100:497–512.PubMedGoogle Scholar
  28. 28.
    Russo J, Tay LK, Ciocca D, Russo IH. Molecular and cellular basis of the mammary gland susceptibility to carcinogenesis. Environ Health Perspect. 1983;49:185–99.PubMedCrossRefGoogle Scholar
  29. 29.
    Welsch CW. Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: A review and tribute to Charles Brenton Huggins. Cancer Res. 1985;45:3415–43.PubMedGoogle Scholar
  30. 30.
    Russo IH, Russo J. Mammary gland neoplasia in long-term rodent studies. Environ Health Perspect. 1996;104:938–67.PubMedCrossRefGoogle Scholar
  31. 31.
    McCormick GM, Moon RC. Effect of nursing and litter size on growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat mammary tumors. Br J Cancer. 1967;21:586–91.PubMedCrossRefGoogle Scholar
  32. 32.
    Cabanes A, Wang M, Olivo S, DeAssis S, Gustafsson JA, Khan G, et al. Prepubertal estradiol and genistein exposures up-regulate BRCA1 mRNA and reduce mammary tumorigenesis. Carcinogenesis. 2004;25:741–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Blakely CM, Stoddard AJ, Belka GK, Dugan KD, Notarfrancesco KL, Moody SE, 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
  34. 34.
    Lakshmanaswamy R, Guzman RC, Nandi S. Hormonal prevention of breast cancer: significance of promotional environment. Adv Exp Med Biol. 2008;617:469–75.PubMedCrossRefGoogle Scholar
  35. 35.
    Medina D, Smith GH. Chemical carcinogen-induced tumorigenesis in parous, involuted mouse mammary glands. J Natl Cancer Inst. 1999;91:967–69.PubMedCrossRefGoogle Scholar
  36. 36.
    Medina D, Kittrell FS. p53 function is required for hormone-mediated protection of mouse mammary tumorigenesis. Cancer Res. 2003;63:6140–3.PubMedGoogle Scholar
  37. 37.
    Medina D. Chemical carcinogenesis of rat and mouse mammary glands. Breast Dis. 2007;28:63–8.PubMedGoogle Scholar
  38. 38.
    Medina D. Premalignant and malignant mammary lesions induced by MMTV and chemical carcinogens. J Mammary Gland Biol Neoplasia. 2008;13:271–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Shen Q, Brown PH. Transgenic mouse models for the prevention of breast cancer. Mutat Res. 2005;576:93–110.PubMedGoogle Scholar
  40. 40.
    Rajkumar L, Kittrell FS, Guzman RC, Brown PH, Nandi S, Medina D. Hormone-induced protection of mammary tumorigenesis in genetically engineered mouse models. Breast Cancer Res. 2007;9:R12.PubMedCrossRefGoogle Scholar
  41. 41.
    Allred DC, Medina D. The relevance of mouse models to understanding the development and progression of human breast cancer. J Mammary Gland Biol Neoplasia. 2008;13:279–88.PubMedCrossRefGoogle Scholar
  42. 42.
    Borowsky AD. Choosing a mouse model: Experimental biology in context—The utility and limitations of mouse models of breast cancer. Cold Spring Harb Perspect Biol 2011.Google Scholar
  43. 43.
    Medina D, Kittrell FS, Hill J, Shepard A, Thordarson G, Brown P. Tamoxifen inhibition of estrogen receptor-alpha-negative mouse mammary tumorigenesis. Cancer Res. 2005;65:3493–6.PubMedGoogle Scholar
  44. 44.
    Rao GN, Piegorsch WW, Haseman JK. Influence of body weight on the incidence of spontaneous tumors in rats and mice of long term studies. Am J Clin Nutr. 1987;45:252–60.PubMedGoogle Scholar
  45. 45.
    Tarone RE, Chu KC, Ward JM. Variability in the rates of some common naturally occurring tumors in Fischer 344 rats and (C57BLU6N x C3/HeN) F1 (B6C3F,) mice. J Natl Cancer Inst. 1981;66:1175–81.PubMedGoogle Scholar
  46. 46.
    Huggins C, Briziarelli G, Sutton H. Rapid induction of mammary carcinoma in the rat and the influence of hormones on the tumors. J Exp Med. 1959;709:25–42.CrossRefGoogle Scholar
  47. 47.
    Huggins C, Grand L, Fukunishi R. Aromatic influences in the yields of mammary cancers following administration of 7,12-dimethylbenzanthracene. Proc Natl Acad Sci USA. 1964;57:737–42.CrossRefGoogle Scholar
  48. 48.
    Gullino PM, Pettigrew HM, Grantham FH. N-nitrosomethylurea as mammary gland carcinogen in rats. J Natl Cancer Inst. 1975;54:401–14.PubMedGoogle Scholar
  49. 49.
    Thordarson G, Lee AV, McCarty M, Van Horn K, Chu O, Chou YC, et al. Growth and characterization of N-methyl-N-nitrosourea-induced mammary tumors in intact and ovariectomized rats. Carcinogenesis. 2001;22:2039–47.PubMedCrossRefGoogle Scholar
  50. 50.
    Russo J, Gusterson BA, Rogers AE, Russo IH, Wellings SR, Van Zwieten MJ. Comparative study of human and rat mammary tumorigenesis. Lab Invest. 1990;62:1–32.Google Scholar
  51. 51.
    Moral R, Wang R, Russo IH, Lamartiniere CA, Pereira J, Russo J. Effect of prenatal exposure to the endocrine disruptor bisphenol A on mammary gland morphology and gene expression signature. J Endocrinol 2008;196:101–12.Google Scholar
  52. 52.
    Kawaguchi H, Miyoshi N, Miyamoto Y, Souda M, Umekita Y, Yasuda N, et al. Effects of fetal exposure to diethylstilbestrol on mammary tumorigenesis in rats. Vet Med Sci. 2009;71:1599–608.CrossRefGoogle Scholar
  53. 53.
    Umekita Y, Souda M, Hatanaka K, Hamada T, Yoshioka T, Kawaguchi H, 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.Google Scholar
  54. 54.
    Goodman A, Schorge J, Greene MF. The long-term effects of in utero exposures—the DES story. N Engl J Med. 2011;364:2083–4.PubMedCrossRefGoogle Scholar
  55. 55.
    Russo IH, Russo J. Primary prevention of breast cancer by hormone-induced differentiation. Recent Results Cancer Res. 2007;174:111–30.PubMedCrossRefGoogle Scholar
  56. 56.
    Russo J, Tait L, Russo IH. Susceptibility of the mammary gland to carcinogenesis: III the cell of origin of rat mammary carcinoma. Am J Path. 1983;113:50–66.PubMedGoogle Scholar
  57. 57.
    Russo J, Balogh GA, Chen J, Fernandez SV, Fernbaugh R, Heulings R, et al. The concept of stem cell in the mammary gland and its implication in morphogenesis, cancer and prevention. Front Biosci. 2006;11:151–72.PubMedCrossRefGoogle Scholar
  58. 58.
    Bennett DC, Peachey LA, Durbin H, Rudland PS. A possible mammary stem cell line. Cell. 1978;15:283–98.PubMedCrossRefGoogle Scholar
  59. 59.
    Bussard KM, Smith GH. The mammary gland microenvironment directs progenitor cell fate in vivo. Int J Cell Biol. 2011;2011:451676.PubMedGoogle Scholar
  60. 60.
    Navarro VM, Castellano JM, Fernandez-Fernandez R, Barreiro ML, Roa J, Sanchez-Criado JE, et al. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor GPR54 in rat hypothalamus and potent LH releasing activity of KiSS-1 peptide. Endocrinology. 2004;145:4565–74.PubMedCrossRefGoogle Scholar
  61. 61.
    Kinoshita M, Tsukamura H, Adachi S, Matsui H, Uenoyama Y, Iwata K, et al. Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology. 2005;146:4431–6.PubMedCrossRefGoogle Scholar
  62. 62.
    Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression. J Mam Gland Biology Neoplasia. 1998;3:49–61.CrossRefGoogle Scholar
  63. 63.
    Russo IH, Frederick J, Russo J. Hormone prevention of mammary carcinogenesis by norethynodrel-mestranol. Breast Cancer Res Treat. 1989;14:43–56.PubMedCrossRefGoogle Scholar
  64. 64.
    Vanegas JE, Kocdor M, Pereira JS, Kocdor H, Russo J, Snider K, et al. Preventive effect of hCG on rat mammary carcinogenesis. Proc Am Assoc Cancer Res 2009.Google Scholar
  65. 65.
    Srivastava P, Russo J, Russo IH. Chorionic gonadotropin inhibits mammary carcinogenesis through activation of programmed cell death. Carcinogenesis. 1997;18:1799–808.PubMedCrossRefGoogle Scholar
  66. 66.
    Srivastava P, Russo J, Russo IH. Inhibition of rat mammary tumorigenesis by human chorionic gonadotropin is associated with increased expression of inhibin. Mol Carcinog. 1999;26:10–9.PubMedCrossRefGoogle Scholar
  67. 67.
    Russo IH, Russo J. Chorionic gonadotropin: a tumoristatic and preventive agent in breast cancer. In: Teicher BA, editor. Drug resistance in oncology. New York: Dekker; 1993. p. 537–60.Google Scholar
  68. 68.
    McCormick GM, Moon RC. Effect of pregnancy and lactation on growth of mammary tumours induced by 7,12-dimethylbenzanthracene (DMBA). Br J Cancer. 1965;79:160–6.CrossRefGoogle Scholar
  69. 69.
    Dao TL, Sunderland H. Mammary carcinogenesis by 3-methylcholanthrene. I. Hormonal aspects in tumor induction and growth. J Natl Cancer Inst. 1959;23:567–85.PubMedGoogle Scholar
  70. 70.
    Grubbs CJ, Hill DL, McDonough KC, Peckham JC. N-Nitroso-N-methylurea-induced mammary carcinogenesis: effect of pregnancy on preneoplastic cells. J Natl Cancer Inst. 1983;71:625–8.PubMedGoogle Scholar
  71. 71.
    Jordan VC. Effect of tamoxifen (ICI 46,474) on the initiation and growth of DMBA-induced rat mammary carcinoma. Eur J Cancer. 1976;12:419–24.PubMedGoogle Scholar
  72. 72.
    Weroha SJ, Li SA, Tawfik O, Li JJ. Overexpression of cyclins D1 and D3 during estrogen-induced breast oncogenesis in female ACI rats. Carcinogenesis. 2006;27:491–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Li SA, Weroha SJ, Tawfik O, Li JJ. Prevention of solely estrogen-induced mammary tumors in female aci rats by tamoxifen: evidence for estrogen receptor mediation. J Endocrinol. 2002;175:297–305.PubMedCrossRefGoogle Scholar
  74. 74.
    Russo J, Fernandez SV, Russo PA, Fernbaugh R, Sheriff FS, Lareef HM, et al. 17-Beta-estradiol induces transformation and tumorigenesis in human breast epithelial cells. FASEB J. 2006;20:1622–34.PubMedCrossRefGoogle Scholar
  75. 75.
    Russo IH, Gimotty P, Dupuis M, Russo J. Effect of medroxyprogesterone acetate on the response of the rat mammary gland to carcinogenesis. Br J Cancer. 1989;59:210–6.PubMedCrossRefGoogle Scholar
  76. 76.
    Lanari C, Lamb CA, Fabris VT, Helguero LA, Soldati R, Bottino MC, et al. The MPA mouse breast cancer model: evidence for a role of progesterone receptors in breast cancer. Endocr Relat Cancer. 2009;16:333–50.PubMedCrossRefGoogle Scholar
  77. 77.
    Russo J, Balogh GA, Heulings R, Mailo DA, Moral R, Russo PA, et al. Molecular basis of pregnancy-induced breast cancer protection. Eur J Cancer Prev. 2006;15:306–42.PubMedCrossRefGoogle Scholar
  78. 78.
    Wagner KU, Boulanger CA, Henry MD, Sgagias M, Hennighausen L, Smith GH. An adjunct mammary epithelial cell population in parous females: its role in functional adaptation and tissue renewal. Development. 2002;129:1377–86.PubMedGoogle Scholar
  79. 79.
    Boulanger CA, Wagner KU, Smith GH. Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-beta 1 expression. Oncogene. 2005;24:552–60.PubMedCrossRefGoogle Scholar
  80. 80.
    Booth BW, Boulanger CA, Smith GH. Selective segregation of DNA strands persists in long-label-retaining mammary cells during pregnancy. Breast Cancer Res. 2008;10:R90.PubMedCrossRefGoogle Scholar
  81. 81.
    Blackshaw S, Scholpp S, Placzek M, Ingraham H, Simerly R, Shimogori T. Molecular pathways controlling development of thalamus and hypothalamus: from neural specification to circuit formation. J Neurosci. 2010;30:14925–30.PubMedCrossRefGoogle Scholar
  82. 82.
    Hendriks AE, Lavens JS, Valkenburg O, Fong SL, Fauser BC, de Ridder MA, et al. Fertility and ovarian function in high-dose estrogen-treated tall women. J Clin Endocrinol Metab. 2011;96:1098–105.PubMedCrossRefGoogle Scholar
  83. 83.
    Russo J, Russo IH. Development of human mammary gland. In: Neville MC, Daniel C, editors. The mammary gland development, regulation and function. New York: Plenum; 1987. p. 67–93.Google Scholar
  84. 84.
    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
  85. 85.
    Howell A, Evans GD. Hormone replacement therapy and breast cancer. Recent Results Cancer Res. 2011;188:115–24.PubMedCrossRefGoogle Scholar
  86. 86.
    Lathi RB, Fisher SJ, Giudice LC. Implantation and placental physiology in early human pregnancy: the role of the maternal decidua and the trophoblast. In: De Groot L, Jameson LJ, editors. Endocrinology. Philadelphia: Elsevier; 2006. p. 3341–51.Google Scholar
  87. 87.
    Parry S, Strauss III F. Placental hormones. In: De Groot L, Jameson LJ, editors. Endocrinology. Philadelphia: Elsevier; 2006. p. 3353–67.Google Scholar
  88. 88.
    Alvarado MV, Ho T-Y, Russo J, Russo IH. Human chorionic gonadotropin regulates the synthesis of inhibin in the ovary and the mammary gland of rats. Endocrine. 1994;2:1–10.Google Scholar
  89. 89.
    Alvarado ME, Alvarado NE, Russo J, Russo IH. Human chorionic gonadotropin inhibits proliferation and induces expression of inhibin in human breast epithelial cells in vitro. In Vitro. 1994;30A:4–8.Google Scholar
  90. 90.
    Horikoshi Y, Matsumoto H, Takatsu Y, Ohtaki T, Kitada C, Usuki S, et al. Dramatic Elevation of plasma metastin concentrations in human pregnancy: metastin as a novel placenta-derived hormone in humans. J Clin Endocrinol Metab. 2003;88:914–9.PubMedCrossRefGoogle Scholar
  91. 91.
    McGregor, Land CE, Choi K, Tokuoka S, Liu PI, Wakabayashi I, et al. Breast cancer incidence among atomic bomb survivors, Hiroshima and Nagaski 1950–1989. J Natl Cancer Inst. 1977;59:799–811.PubMedGoogle Scholar
  92. 92.
    Cutuli B, Borel C, Dhermain F, Magrini SM, Wasserman TH, Bogart JA, et al. Breast cancer occurred after treatment for Hodgkin's disease: analysis of 133 cases. Radiother Oncol. 2001;59:247–55.PubMedCrossRefGoogle Scholar
  93. 93.
    Johnson KC, Miller AB, Collishaw NE, Palmer JR, Hammond SK, Salmon AG, et al. Active smoking and secondhand smoke increase breast cancer risk: the report of the Canadian expert panel on tobacco smoke and breast cancer risk (2009). Tob Control. 2011;20:e2.PubMedCrossRefGoogle Scholar
  94. 94.
    Johansson AL, Andersson TM, Hsieh CC, Cnattingius S, Lambe M. Increased mortality in women with breast cancer detected during pregnancy and different periods postpartum. Cancer Epidemiol Biomarkers Prev. 2011.Google Scholar
  95. 95.
    Hahn RA, Moolgavkar SH. Nulliparity, decade of first birth, and breast cancer in Connecticut cohorts, 1855 to 1945: an ecological study. Am J Public Health. 1989;79:1503–7.PubMedCrossRefGoogle Scholar
  96. 96.
    Mathews TJ, Hamilton BE. Delayed childbearing: more women are having their first child later in life. NCHS data brief, No. 21. Hyattaville: National Center for Health Statistics; 2009.Google Scholar
  97. 97.
    Balogh GA, Heulings R, Mailo DA, Russo PA, Sheriff F, Russo IH, et al. Genomic signature induced by pregnancy in the human breast. Int J Oncol. 2006;28:399–410.PubMedGoogle Scholar
  98. 98.
    Russo J, Balogh GA, Russo IH. Full-term pregnancy induces a specific genomic signature in the human breast. Cancer Epidemiol. Biomarkers Prev. 2008;17:51–66.CrossRefGoogle Scholar
  99. 99.
    George K, Kamath MS. Fertility and age. J Hum Reprod Sci. 2010;3:121–3.PubMedCrossRefGoogle Scholar
  100. 100.
    Homan GF, Davies M, Norman R. The impact of lifestyles factors on reproductive performance in the general population and those undergoing infertility treatment. Hum Reprod Update. 2007;13:209–23.PubMedCrossRefGoogle Scholar
  101. 101.
    Gleicher N, Weghofer A, Barad DH. Defining ovarian reserve to better understand ovarian aging. Reprod Biol Endocrinol. 2011;9:23.PubMedCrossRefGoogle Scholar
  102. 102.
    Wise PM, Smith MJ, Dubal DB, Wilson ME, Rau SW, Cashion AB, et al. Neuroendocrine modulation and repercussions of female reproductive aging. Recent Prog Horm Res. 2002;57:235–56.PubMedCrossRefGoogle Scholar
  103. 103.
    Danforth DR, Arbogast LK, Mroueh J, Kim MH, Kennard EA, Seifer DB, et al. Dimeric inhibin: a direct marker of ovarian ageing. Fertil Steril. 1998;70:119–23.PubMedCrossRefGoogle Scholar
  104. 104.
    Rance NE. Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides. 2009;30:111–22.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Molecular Endocrinology Section, Breast Cancer Research LaboratoryFox Chase Cancer CenterPhiladelphiaUSA
  2. 2.Breast Cancer Research LaboratoryFox Chase Cancer CenterPhiladelphiaUSA

Personalised recommendations