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. 1983 Apr;50:209–218. doi: 10.1289/ehp.8350209

Factors that promote the development of human breast cancer.

D B Thomas
PMCID: PMC1569207  PMID: 6873014

Abstract

Epidemiologic and endocrinologic studies of breast cancer etiology are reviewed in the context of the Moolgavkar two-stage model for mammary carcinogenesis. Promoters are hypothesized to enhance the growth of stem and intermediate cells, and initiators are assumed to cause stem and intermediate cells to give rise to intermediate and tumor cells, respectively. Although all epidemiologic features of breast cancer can be explained in terms of the cellular events supposed by the model, the specific causes of breast cancer are largely unknown. Aberrations in endogenous steroid sex hormones most probably act as promoters, although their exact nature and etiology are unclear. Ionizing radiation is the only known initiator. The two-stage model implies that others exist and that they are responsible for both the international variation in risk of breast cancer, and its familial aggregation. Results of endocrinologic studies suggest either that aberrations in endogenous sex hormones serve as such initiators or are correlated with them, or that familial and international variations in risk are mediated by promoters.

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Selected References

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  1. Anderson D. E. Breast cancer in families. Cancer. 1977 Oct;40(4 Suppl):1855–1860. doi: 10.1002/1097-0142(197710)40:4+<1855::aid-cncr2820400814>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  2. Anderson D. E. Genetic study of breast cancer: identification of a high risk group. Cancer. 1974 Oct;34(4):1090–1097. doi: 10.1002/1097-0142(197410)34:4<1090::aid-cncr2820340419>3.0.co;2-j. [DOI] [PubMed] [Google Scholar]
  3. Armstrong B., Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer. 1975 Apr 15;15(4):617–631. doi: 10.1002/ijc.2910150411. [DOI] [PubMed] [Google Scholar]
  4. BULBROOK R. D., THOMAS B. S. URINARY 11-DEOXY-17-OXOSTEROIDS IN BRITISH AND JAPANESE WOMEN WITH REFERENCE TO THE INCIDENCE OF BREAST CANCER. Nature. 1964 Jan 11;201:189–190. doi: 10.1038/201189a0. [DOI] [PubMed] [Google Scholar]
  5. Baral E., Larsson L. E., Mattsson B. Breast cancer following irradiation of the breast. Cancer. 1977 Dec;40(6):2905–2910. doi: 10.1002/1097-0142(197712)40:6<2905::aid-cncr2820400621>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  6. Baverstock K. F., Papworth D., Vennart J. Risks of radiation at low dose rates. Lancet. 1981 Feb 21;1(8217):430–433. doi: 10.1016/s0140-6736(81)91804-3. [DOI] [PubMed] [Google Scholar]
  7. Boice J. D., Jr, Monson R. R. Breast cancer in women after repeated fluoroscopic examinations of the chest. J Natl Cancer Inst. 1977 Sep;59(3):823–832. doi: 10.1093/jnci/59.3.823. [DOI] [PubMed] [Google Scholar]
  8. Boyns A. R., Cole E. N., Griffiths K., Roberts M. M., Buchan R., Wilson R. G., Forrest A. P. Plasma prolactin in breast cancer. Eur J Cancer. 1973 Feb;9(2):99–102. doi: 10.1016/0014-2964(73)90078-9. [DOI] [PubMed] [Google Scholar]
  9. Brennan M. J., Wang D. Y., Hayward J. L., Bulbrook R. D., Deshpande N. Urinary and plasma androgens in benign breast disease. Possible relation to breast cancer. Lancet. 1973 May 19;1(7812):1076–1079. doi: 10.1016/s0140-6736(73)90393-0. [DOI] [PubMed] [Google Scholar]
  10. Brinton L. A., Hoover R. N., Szklo M., Fraumeni J. F., Jr Menopausal estrogen use and risk of breast cancer. Cancer. 1981 May 15;47(10):2517–2522. doi: 10.1002/1097-0142(19810515)47:10<2517::aid-cncr2820471035>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  11. Bulbrook R. D., Hayward J. L., Spicer C. C. Relation between urinary androgen and corticoid excretion and subsequent breast cancer. Lancet. 1971 Aug 21;2(7721):395–398. doi: 10.1016/s0140-6736(71)90113-9. [DOI] [PubMed] [Google Scholar]
  12. Bulbrook R. D., Moore J. W., Clark G. M., Wang D. Y., Tong D., Hayward J. L. Plasma oestradiol and progesterone levels in women with varying degrees of risk of breast cancer. Eur J Cancer. 1978 Dec;14(12):1369–1375. doi: 10.1016/0014-2964(78)90120-2. [DOI] [PubMed] [Google Scholar]
  13. Bulbrook R. D., Swain M. C., Wang D. Y., Hayward J. L., Kumaoka S., Takatani O., Abe O., Utsunomiya J. Breast cancer in Britain and Japan: plasma oestradiol-17beta, oestrone and progesterone,and their urinary metabolites in normal British and Japanese women. Eur J Cancer. 1976 Sep;12(9):725–735. doi: 10.1016/0014-2964(76)90023-2. [DOI] [PubMed] [Google Scholar]
  14. Burns P. E., Lees A. W., Hurlburt M. E., May C. L., Grace M. Reproductive events and family history as risk factors for breast cancer in northern Alberta. Can Med Assoc J. 1981 Jun 1;124(11):1451–1457. [PMC free article] [PubMed] [Google Scholar]
  15. Carroll K. K., Gammal E. B., Plunkett E. R. Dietary fat and mammary cancer. Can Med Assoc J. 1968 Mar 23;98(12):590–594. [PMC free article] [PubMed] [Google Scholar]
  16. Cook D. C., Dent O., Hewitt D. Breast cancer following multiple chest fluoroscopy: the Ontario experience. Can Med Assoc J. 1974 Sep 7;111(5):406–409. [PMC free article] [PubMed] [Google Scholar]
  17. Correa P. Epidemiological correlations between diet and cancer frequency. Cancer Res. 1981 Sep;41(9 Pt 2):3685–3690. [PubMed] [Google Scholar]
  18. Cowan L. D., Gordis L., Tonascia J. A., Jones G. S. Breast cancer incidence in women with a history of progesterone deficiency. Am J Epidemiol. 1981 Aug;114(2):209–217. doi: 10.1093/oxfordjournals.aje.a113184. [DOI] [PubMed] [Google Scholar]
  19. Delarue N. C., Gale G., Ronald A. Multiple fluoroscopy of the chest: carcinogenicity for the female breast and implications for breast cancer screening programs. Can Med Assoc J. 1975 Jun 21;112(12):1405–1413. [PMC free article] [PubMed] [Google Scholar]
  20. Farewell V. T. The combined effect of breast cancer risk factors. Cancer. 1977 Aug;40(2):931–936. doi: 10.1002/1097-0142(197708)40:2<931::aid-cncr2820400251>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  21. Fishman J., Fukushima D. K., O'Connor J., Lynch H. T. Low urinary estrogen glucuronides in women at risk for familial breast cancer. Science. 1979 Jun 8;204(4397):1089–1091. doi: 10.1126/science.451553. [DOI] [PubMed] [Google Scholar]
  22. Goode D. J., Corbett W. T., Schey H. M., Suh S. H., Woodie B., Morris D. L., Morrisey L. Breast cancer in hospitalized psychiatric patients. Am J Psychiatry. 1981 Jun;138(6):804–806. doi: 10.1176/ajp.138.6.804. [DOI] [PubMed] [Google Scholar]
  23. Gray G. E., Pike M. C., Henderson B. E. Breast-cancer incidence and mortality rates in different countries in relation to known risk factors and dietary practices. Br J Cancer. 1979 Jan;39(1):1–7. doi: 10.1038/bjc.1979.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Hedley A. J., Jones S. J., Spiegelhalter D. J., Clements P., Bewsher P. D., Simpson J. G., Weir R. D. Breast cancer in thyroid disease: fact or fallacy? Lancet. 1981 Jan 17;1(8212):131–133. doi: 10.1016/s0140-6736(81)90712-1. [DOI] [PubMed] [Google Scholar]
  25. Hill M. J., Goddard P., Williams R. E. Gut bacteria and aetiology of cancer of the breast. Lancet. 1971 Aug 28;2(7722):472–473. doi: 10.1016/s0140-6736(71)92634-1. [DOI] [PubMed] [Google Scholar]
  26. Hill P., Wynder E. L., Kumar H., Helman P., Rona G., Kuno K. Prolactin levels in populations at risk for breast cancer. Cancer Res. 1976 Nov;36(11 Pt 1):4102–4106. [PubMed] [Google Scholar]
  27. Holm N. V., Hauge M., Harvald B. Etiologic factors of breast cancer elucidated by a study of unselected twins. J Natl Cancer Inst. 1980 Aug;65(2):285–298. [PubMed] [Google Scholar]
  28. Hoover R., Glass A., Finkle W. D., Azevedo D., Milne K. Conjugated estrogens and breast cancer risk in women. J Natl Cancer Inst. 1981 Oct;67(4):815–820. [PubMed] [Google Scholar]
  29. Hoover R., Gray L. A., Sr, Cole P., MacMahon B. Menopausal estrogens and breast cancer. N Engl J Med. 1976 Aug 19;295(8):401–405. doi: 10.1056/NEJM197608192950801. [DOI] [PubMed] [Google Scholar]
  30. Hutchinson W. B., Thomas D. B., Hamlin W. B., Roth G. J., Peterson A. V., Williams B. Risk of breast cancer in women with benign breast disease. J Natl Cancer Inst. 1980 Jul;65(1):13–20. [PubMed] [Google Scholar]
  31. Jick H., Walker A. M., Watkins R. N., D'Ewart D. C., Hunter J. R., Danford A., Madsen S., Dinan B. J., Rothman K. J. Replacement estrogens and breast cancer. Am J Epidemiol. 1980 Nov;112(5):586–594. doi: 10.1093/oxfordjournals.aje.a113031. [DOI] [PubMed] [Google Scholar]
  32. Knudson A. G., Jr, Hethcote H. W., Brown B. W. Mutation and childhood cancer: a probabilistic model for the incidence of retinoblastoma. Proc Natl Acad Sci U S A. 1975 Dec;72(12):5116–5120. doi: 10.1073/pnas.72.12.5116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Kolonel L. N., Hankin J. H., Lee J., Chu S. Y., Nomura A. M., Hinds M. W. Nutrient intakes in relation to cancer incidence in Hawaii. Br J Cancer. 1981 Sep;44(3):332–339. doi: 10.1038/bjc.1981.189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Korenman S. G. Oestrogen window hypothesis of the aetiology of breast cancer. Lancet. 1980 Mar 29;1(8170):700–701. [PubMed] [Google Scholar]
  35. Kwa H. G., De Jong-Bakker M., Engelsman E., Cleton F. J. Plasma-prolactin in human breast cancer. Lancet. 1974 Mar 16;1(7855):433–435. doi: 10.1016/s0140-6736(74)92385-x. [DOI] [PubMed] [Google Scholar]
  36. Labarthe D. R. Methodologic variation in case-control studies of reserpine and breast cancer. J Chronic Dis. 1979;32(1-2):95–104. doi: 10.1016/0021-9681(79)90021-3. [DOI] [PubMed] [Google Scholar]
  37. Land C. E. Low-dose radiation--a cause of breast cancer? Cancer. 1980 Aug 15;46(4 Suppl):868–873. doi: 10.1002/1097-0142(19800815)46:4+<868::aid-cncr2820461304>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  38. Lawson D. H., Jick H., Hunter J. R., Madsen S. Exogenous estrogens and breast cancer. Am J Epidemiol. 1981 Nov;114(5):710–713. doi: 10.1093/oxfordjournals.aje.a113242. [DOI] [PubMed] [Google Scholar]
  39. Lemon H. M. Endocrine influences on human mammary cancer formation. A critique. Cancer. 1969 Apr;23(4):781–790. doi: 10.1002/1097-0142(196904)23:4<781::aid-cncr2820230407>3.0.co;2-1. [DOI] [PubMed] [Google Scholar]
  40. Longcope C. Metabolic clearance and blood production rates of estrogens in postmenopausal women. Am J Obstet Gynecol. 1971 Nov;111(6):778–781. doi: 10.1016/0002-9378(71)90488-1. [DOI] [PubMed] [Google Scholar]
  41. Longcope C., Pratt J. H. Blood production rates of estrogens in women with differing ratios of urinary estrogen conjugates. Steroids. 1977 Apr;29(4):483–492. doi: 10.1016/0039-128x(77)90068-x. [DOI] [PubMed] [Google Scholar]
  42. MACKENZIE I. BREAST CANCER FOLLOWING MULTIPLE FLUOROSCOPIES. Br J Cancer. 1965 Mar;19:1–8. doi: 10.1038/bjc.1965.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. McGregor H., Land C. E., Choi K., Tokuoka S., Liu P. I., Wakabayashi T., Beebe G. W. Breast cancer incidence among atomic bomb survivors, Hiroshima and Nagasaki, 1950-69. J Natl Cancer Inst. 1977 Sep;59(3):799–811. doi: 10.1093/jnci/59.3.799. [DOI] [PubMed] [Google Scholar]
  44. Mettler F. A., Jr, Hempelmann L. H., Dutton A. M., Pifer J. W., Toyooka E. T., Ames W. R. Breast neoplasms in women treated with x rays for acute postpartum mastitis. A pilot study. J Natl Cancer Inst. 1969 Oct;43(4):803–811. [PubMed] [Google Scholar]
  45. Miller A. B., Kelly A., Choi N. W., Matthews V., Morgan R. W., Munan L., Burch J. D., Feather J., Howe G. R., Jain M. A study of diet and breast cancer. Am J Epidemiol. 1978 Jun;107(6):499–509. doi: 10.1093/oxfordjournals.aje.a112569. [DOI] [PubMed] [Google Scholar]
  46. Miller W. R., Hamilton T., Champion H. R., Wallace I. W., Forrest A. P., Prescott R. J., Cameron E. H., Griffiths K. Urinary aetiocholanolone in patients with early breast cancer from South East Scotland and South Wales. Br J Cancer. 1975 Nov;32(5):619–627. doi: 10.1038/bjc.1975.269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Mittra I., Hayward J. L., McNeilly A. S. Hypothalamic-pituitary-prolactin axis in breast cancer. Lancet. 1974 May 11;1(7863):889–891. doi: 10.1016/s0140-6736(74)90345-6. [DOI] [PubMed] [Google Scholar]
  48. Moolgavkar S. H., Day N. E., Stevens R. G. Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. J Natl Cancer Inst. 1980 Sep;65(3):559–569. [PubMed] [Google Scholar]
  49. Moolgavkar S. H., Knudson A. G., Jr Mutation and cancer: a model for human carcinogenesis. J Natl Cancer Inst. 1981 Jun;66(6):1037–1052. doi: 10.1093/jnci/66.6.1037. [DOI] [PubMed] [Google Scholar]
  50. Mustacchi P., Greenspan F. Thyroid supplementation for hypothyroidism. An latrogenic cause of breast cancer? JAMA. 1977 Apr 4;237(14):1446–1447. [PubMed] [Google Scholar]
  51. Myrden J. A., Hiltz J. E. Breast cancer following multiple fluoroscopies during artificial pneumothorax treatment of pulmonary tuberculosis. Can Med Assoc J. 1969 Jun 14;100(22):1032–1034. [PMC free article] [PubMed] [Google Scholar]
  52. Nomura A., Henderson B. E., Lee J. Breast cancer and diet among the Japanese in Hawaii. Am J Clin Nutr. 1978 Nov;31(11):2020–2025. doi: 10.1093/ajcn/31.11.2020. [DOI] [PubMed] [Google Scholar]
  53. Page D. L., Vander Zwaag R., Rogers L. W., Williams L. T., Walker W. E., Hartmann W. H. Relation between component parts of fibrocystic disease complex and breast cancer. J Natl Cancer Inst. 1978 Oct;61(4):1055–1063. [PubMed] [Google Scholar]
  54. Phillips R. L. Role of life-style and dietary habits in risk of cancer among seventh-day adventists. Cancer Res. 1975 Nov;35(11 Pt 2):3513–3522. [PubMed] [Google Scholar]
  55. Pike M. C., Casagrande J. T., Brown J. B., Gerkins V., Henderson B. E. Comparison of urinary and plasma hormone levels in daughters of breast cancer patients and controls. J Natl Cancer Inst. 1977 Nov;59(5):1351–1355. doi: 10.1093/jnci/59.5.1351. [DOI] [PubMed] [Google Scholar]
  56. Pike M. C., Henderson B. E., Casagrande J. T., Rosario I., Gray G. E. Oral contraceptive use and early abortion as risk factors for breast cancer in young women. Br J Cancer. 1981 Jan;43(1):72–76. doi: 10.1038/bjc.1981.10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Reddy B. S. Dietary fat and its relationship to large bowel cancer. Cancer Res. 1981 Sep;41(9 Pt 2):3700–3705. [PubMed] [Google Scholar]
  58. Ross R. K., Paganini-Hill A., Gerkins V. R., Mack T. M., Pfeffer R., Arthur M., Henderson B. E. A case-control study of menopausal estrogen therapy and breast cancer. JAMA. 1980 Apr 25;243(16):1635–1639. [PubMed] [Google Scholar]
  59. Rudali G., Apiou F., Muel B. Mammary cancer produced in mice with estriol. Eur J Cancer. 1975 Jan;11(1):39–41. doi: 10.1016/0014-2964(75)90035-3. [DOI] [PubMed] [Google Scholar]
  60. Shapiro S., Slone D., Kaufman D. W., Rosenberg L., Miettinen O. S., Stolley P. D., Knapp R. C., Leavitt T., Jr, Watring W. G., Rosenshein N. B. Use of thyroid supplements in relation to the risk of breast cancer. JAMA. 1980 Oct 10;244(15):1685–1687. [PubMed] [Google Scholar]
  61. Sherman B. M., Korenman S. G. Inadequate corpus luteum function: a pathophysiological interpretation of human breast cancer epidemiology. Cancer. 1974 May;33(5):1306–1312. doi: 10.1002/1097-0142(197405)33:5<1306::aid-cncr2820330515>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  62. Sherman B., Wallace R., Bean J., Schlabaugh L. Relationship of body weight to menarcheal and menopausal age: implications for breast cancer risk. J Clin Endocrinol Metab. 1981 Mar;52(3):488–493. doi: 10.1210/jcem-52-3-488. [DOI] [PubMed] [Google Scholar]
  63. Sheth N. A., Ranadive K. J., Suraiya J. N., Sheth A. R. Circulating levels of prolactin in human breast cancer. Br J Cancer. 1975 Aug;32(2):160–167. doi: 10.1038/bjc.1975.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Shore R. E., Hempelmann L. H., Kowaluk E., Mansur P. S., Pasternack B. S., Albert R. E., Haughie G. E. Breast neoplasms in women treated with x-rays for acute postpartum mastitis. J Natl Cancer Inst. 1977 Sep;59(3):813–822. doi: 10.1093/jnci/59.3.813. [DOI] [PubMed] [Google Scholar]
  65. Shore R. E., Woodard E. D., Hempelmann L. H., Pasternack B. S. Synergism between radiation and other risk factors for breast cancer. Prev Med. 1980 Nov;9(6):815–822. doi: 10.1016/0091-7435(80)90024-9. [DOI] [PubMed] [Google Scholar]
  66. Simon N. Breast cancer induced by radiation. Relation to mammography and treatment of acne. JAMA. 1977 Feb 21;237(8):789–790. [PubMed] [Google Scholar]
  67. Thomas D. B. Role of exogenous female hormones in altering the risk of benign and malignant neoplasms in humans. Cancer Res. 1978 Nov;38(11 Pt 2):3991–4000. [PubMed] [Google Scholar]
  68. Trichopoulos D., Brown J. B., Garas J., Papaioannou A., MacMahon B. Elevated urine estrogen and pregnanediol levels in daughters of breast cancer patients. J Natl Cancer Inst. 1981 Sep;67(3):603–606. [PubMed] [Google Scholar]
  69. Trichopoulos D., Cole P., Brown J. B., Goldman M. B., MacMahon B. Estrogen profiles of primiparous and nulliparous women in Athens, Greece. J Natl Cancer Inst. 1980 Jul;65(1):43–46. [PubMed] [Google Scholar]
  70. Vessey M. P., McPherson K., Doll R. Breast cancer and oral contraceptives: findings in Oxford-Family Planning Association contraceptive study. Br Med J (Clin Res Ed) 1981 Jun 27;282(6282):2093–2094. doi: 10.1136/bmj.282.6282.2093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Wanebo C. K., Johnson K. G., Sato K., Thorslund T. W. Breast cancer after exposure to the atomic bombings of Hiroshima and Nagasaki. N Engl J Med. 1968 Sep 26;279(13):667–671. doi: 10.1056/NEJM196809262791301. [DOI] [PubMed] [Google Scholar]
  72. Wang D. Y., Bulbrook R. D., Hayward J. L. Urinary and plasma androgens and their relation to familial risk of breast cancer. Eur J Cancer. 1975 Dec;11(12):873–877. doi: 10.1016/0014-2964(75)90087-0. [DOI] [PubMed] [Google Scholar]
  73. Wilson R. G., Buchan R., Roberts M. M., Forrest A. P., Boyns A. R., Cole E. N., Griffiths K. Plasma prolactin and breast cancer. Cancer. 1974 May;33(5):1325–1327. doi: 10.1002/1097-0142(197405)33:5<1325::aid-cncr2820330517>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  74. de Waard F., Kwa H. G., Poortman J. Plasma prolactin levels in women at postmenopausal age with a family history of breast cancer or a prescription for antihypertensive Rauwolfia treatment. Oncology. 1980;37(1):33–36. doi: 10.1159/000225398. [DOI] [PubMed] [Google Scholar]

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