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. 1998 Jul 1;159(1):55–59.

A developmental hypothesis to explain the multicentricity of breast cancer

C R Sharpe 1
PMCID: PMC1229484  PMID: 9679488

Abstract

In this article the author proposes that the multicentricity of breast cancer might be explained by a developmental hypothesis. Genetic alterations ("hits") occurring in epithelial stem cells during the development of the breast may be transmitted to populations of daughter cells during growth. As a result, areas of the breast may be predisposed to malignant transformation with the occurrence of further genetic hits. Areas with the same predisposition should be anatomically connected, and earlier hits during breast development should result in larger areas of predisposition. The multicentricity of breast cancer would be explained if multiple lesions--monoclonal for the predisposing genetic hit and polyclonal for subsequent hits--developed within a predisposed area. Multiple lesions arising from the spread of disease by extension would be expected to share many genetic hits. The author discusses the implications that further evidence supporting the developmental hypothesis would have for the prevention and treatment of breast cancer.

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Selected References

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  1. Alpers C. E., Wellings S. R. The prevalence of carcinoma in situ in normal and cancer-associated breasts. Hum Pathol. 1985 Aug;16(8):796–807. doi: 10.1016/s0046-8177(85)80251-3. [DOI] [PubMed] [Google Scholar]
  2. Ambrosone C. B., Freudenheim J. L., Graham S., Marshall J. R., Vena J. E., Brasure J. R., Michalek A. M., Laughlin R., Nemoto T., Gillenwater K. A. Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA. 1996 Nov 13;276(18):1494–1501. [PubMed] [Google Scholar]
  3. Anastassiades O., Iakovou E., Stavridou N., Gogas J., Karameris A. Multicentricity in breast cancer. A study of 366 cases. Am J Clin Pathol. 1993 Mar;99(3):238–243. doi: 10.1093/ajcp/99.3.238. [DOI] [PubMed] [Google Scholar]
  4. Cha R. S., Thilly W. G., Zarbl H. N-nitroso-N-methylurea-induced rat mammary tumors arise from cells with preexisting oncogenic Hras1 gene mutations. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3749–3753. doi: 10.1073/pnas.91.9.3749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cohen S. M., Ellwein L. B. Cell proliferation in carcinogenesis. Science. 1990 Aug 31;249(4972):1007–1011. doi: 10.1126/science.2204108. [DOI] [PubMed] [Google Scholar]
  6. Colditz G. A., Frazier A. L. Models of breast cancer show that risk is set by events of early life: prevention efforts must shift focus. Cancer Epidemiol Biomarkers Prev. 1995 Jul-Aug;4(5):567–571. [PubMed] [Google Scholar]
  7. Connolly J. L., Harris J. R., Schnitt S. J. Understanding the distribution of cancer within the breast is important for optimizing breast-conserving treatment. Cancer. 1995 Jul 1;76(1):1–3. doi: 10.1002/1097-0142(19950701)76:1<1::aid-cncr2820760102>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  8. Deng G., Lu Y., Zlotnikov G., Thor A. D., Smith H. S. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science. 1996 Dec 20;274(5295):2057–2059. doi: 10.1126/science.274.5295.2057. [DOI] [PubMed] [Google Scholar]
  9. Fisher E. R., Gregorio R., Redmond C., Vellios F., Sommers S. C., Fisher B. Pathologic findings from the National Surgical Adjuvant Breast Project (protocol no. 4). I. Observations concerning the multicentricity of mammary cancer. Cancer. 1975 Jan;35(1):247–254. doi: 10.1002/1097-0142(197501)35:1<247::aid-cncr2820350130>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  10. Foote F. W., Stewart F. W. Lobular carcinoma in situ: A rare form of mammary cancer. Am J Pathol. 1941 Jul;17(4):491–496.3. doi: 10.3322/canjclin.32.4.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Greene M. H. Genetics of breast cancer. Mayo Clin Proc. 1997 Jan;72(1):54–65. doi: 10.4065/72.1.54. [DOI] [PubMed] [Google Scholar]
  12. Holland R., Hendriks J. H., Vebeek A. L., Mravunac M., Schuurmans Stekhoven J. H. Extent, distribution, and mammographic/histological correlations of breast ductal carcinoma in situ. Lancet. 1990 Mar 3;335(8688):519–522. doi: 10.1016/0140-6736(90)90747-s. [DOI] [PubMed] [Google Scholar]
  13. Huang Z., Hankinson S. E., Colditz G. A., Stampfer M. J., Hunter D. J., Manson J. E., Hennekens C. H., Rosner B., Speizer F. E., Willett W. C. Dual effects of weight and weight gain on breast cancer risk. JAMA. 1997 Nov 5;278(17):1407–1411. [PubMed] [Google Scholar]
  14. Hunter D. J., Hankinson S. E., Hough H., Gertig D. M., Garcia-Closas M., Spiegelman D., Manson J. E., Colditz G. A., Willett W. C., Speizer F. E. A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of breast cancer. Carcinogenesis. 1997 Nov;18(11):2127–2132. doi: 10.1093/carcin/18.11.2127. [DOI] [PubMed] [Google Scholar]
  15. John E. M., Kelsey J. L. Radiation and other environmental exposures and breast cancer. Epidemiol Rev. 1993;15(1):157–162. doi: 10.1093/oxfordjournals.epirev.a036099. [DOI] [PubMed] [Google Scholar]
  16. Johnson J. E., Page D. L., Winfield A. C., Reynolds V. H., Sawyers J. L. Recurrent mammary carcinoma after local excision. A segmental problem. Cancer. 1995 Apr 1;75(7):1612–1618. doi: 10.1002/1097-0142(19950401)75:7<1612::aid-cncr2820750710>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  17. Lagios M. D., Westdahl P. R., Margolin F. R., Rose M. R. Duct carcinoma in situ. Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer. 1982 Oct 1;50(7):1309–1314. doi: 10.1002/1097-0142(19821001)50:7<1309::aid-cncr2820500716>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  18. Lagios M. D., Westdahl P. R., Rose M. R. The concept and implications of multicentricity in breast carcinoma. Pathol Annu. 1981;16(Pt 2):83–102. [PubMed] [Google Scholar]
  19. Lambird P. A., Shelley W. M. The spatial distribution of lobular in situ mammary carcinoma. Implications for size and site of breast biopsy. JAMA. 1969 Oct 27;210(4):689–693. [PubMed] [Google Scholar]
  20. Love S. M., Barsky S. H. Breast-duct endoscopy to study stages of cancerous breast disease. Lancet. 1996 Oct 12;348(9033):997–999. doi: 10.1016/S0140-6736(96)04145-1. [DOI] [PubMed] [Google Scholar]
  21. MacMahon B., Cole P., Lin T. M., Lowe C. R., Mirra A. P., Ravnihar B., Salber E. J., Valaoras V. G., Yuasa S. Age at first birth and breast cancer risk. Bull World Health Organ. 1970;43(2):209–221. [PMC free article] [PubMed] [Google Scholar]
  22. Mao L., Lee D. J., Tockman M. S., Erozan Y. S., Askin F., Sidransky D. Microsatellite alterations as clonal markers for the detection of human cancer. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9871–9875. doi: 10.1073/pnas.91.21.9871. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Merzenich H., Boeing H., Wahrendorf J. Dietary fat and sports activity as determinants for age at menarche. Am J Epidemiol. 1993 Aug 15;138(4):217–224. doi: 10.1093/oxfordjournals.aje.a116850. [DOI] [PubMed] [Google Scholar]
  24. Mohrenweiser H., Zingg B. Mosaicism: the embryo as a target for induction of mutations leading to cancer and genetic disease. Environ Mol Mutagen. 1995;25 (Suppl 26):21–29. doi: 10.1002/em.2850250606. [DOI] [PubMed] [Google Scholar]
  25. Moolgavkar S. H. A two-stage carcinogenesis model for risk assessment. Cell Biol Toxicol. 1989 Dec;5(4):445–460. doi: 10.1007/BF00118413. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. 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]
  28. Noguchi S., Aihara T., Koyama H., Motomura K., Inaji H., Imaoka S. Discrimination between multicentric and multifocal carcinomas of the breast through clonal analysis. Cancer. 1994 Aug 1;74(3):872–877. doi: 10.1002/1097-0142(19940801)74:3<872::aid-cncr2820740313>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  29. O'Connell P., Pekkel V., Fuqua S., Osborne C. K., Allred D. C. Molecular genetic studies of early breast cancer evolution. Breast Cancer Res Treat. 1994;32(1):5–12. doi: 10.1007/BF00666201. [DOI] [PubMed] [Google Scholar]
  30. Ohtake T., Abe R., Kimijima I., Fukushima T., Tsuchiya A., Hoshi K., Wakasa H. Intraductal extension of primary invasive breast carcinoma treated by breast-conservative surgery. Computer graphic three-dimensional reconstruction of the mammary duct-lobular systems. Cancer. 1995 Jul 1;76(1):32–45. doi: 10.1002/1097-0142(19950701)76:1<32::aid-cncr2820760106>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  31. Preston-Martin S., Pike M. C., Ross R. K., Jones P. A., Henderson B. E. Increased cell division as a cause of human cancer. Cancer Res. 1990 Dec 1;50(23):7415–7421. [PubMed] [Google Scholar]
  32. Rosenberg C. L., de las Morenas A., Huang K., Cupples L. A., Faller D. V., Larson P. S. Detection of monoclonal microsatellite alterations in atypical breast hyperplasia. J Clin Invest. 1996 Sep 1;98(5):1095–1100. doi: 10.1172/JCI118890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Russo J., Tay L. K., Russo I. H. Differentiation of the mammary gland and susceptibility to carcinogenesis. Breast Cancer Res Treat. 1982;2(1):5–73. doi: 10.1007/BF01805718. [DOI] [PubMed] [Google Scholar]
  34. Sacchini V. Multicentricity and recurrence of breast cancer. Lancet. 1996 Nov 9;348(9037):1256–1257. doi: 10.1016/S0140-6736(05)65752-2. [DOI] [PubMed] [Google Scholar]
  35. Schnitt S. J., Abner A., Gelman R., Connolly J. L., Recht A., Duda R. B., Eberlein T. J., Mayzel K., Silver B., Harris J. R. The relationship between microscopic margins of resection and the risk of local recurrence in patients with breast cancer treated with breast-conserving surgery and radiation therapy. Cancer. 1994 Sep 15;74(6):1746–1751. doi: 10.1002/1097-0142(19940915)74:6<1746::aid-cncr2820740617>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  36. Schnitt S. J., Silen W., Sadowsky N. L., Connolly J. L., Harris J. R. Ductal carcinoma in situ (intraductal carcinoma) of the breast. N Engl J Med. 1988 Apr 7;318(14):898–903. doi: 10.1056/NEJM198804073181406. [DOI] [PubMed] [Google Scholar]
  37. Smith-Warner S. A., Spiegelman D., Yaun S. S., van den Brandt P. A., Folsom A. R., Goldbohm R. A., Graham S., Holmberg L., Howe G. R., Marshall J. R. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA. 1998 Feb 18;279(7):535–540. doi: 10.1001/jama.279.7.535. [DOI] [PubMed] [Google Scholar]
  38. Teixeira M. R., Pandis N., Bardi G., Andersen J. A., Mandahl N., Mitelman F., Heim S. Cytogenetic analysis of multifocal breast carcinomas: detection of karyotypically unrelated clones as well as clonal similarities between tumour foci. Br J Cancer. 1994 Nov;70(5):922–927. doi: 10.1038/bjc.1994.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Thilly W. G. Looking ahead: algebraic thinking about genetics, cell kinetics and cancer. IARC Sci Publ. 1988;(89):486–492. [PubMed] [Google Scholar]
  40. Thune I., Brenn T., Lund E., Gaard M. Physical activity and the risk of breast cancer. N Engl J Med. 1997 May 1;336(18):1269–1275. doi: 10.1056/NEJM199705013361801. [DOI] [PubMed] [Google Scholar]
  41. Tsai Y. C., Lu Y., Nichols P. W., Zlotnikov G., Jones P. A., Smith H. S. Contiguous patches of normal human mammary epithelium derived from a single stem cell: implications for breast carcinogenesis. Cancer Res. 1996 Jan 15;56(2):402–404. [PubMed] [Google Scholar]
  42. Tulinius H., Day N. E., Jóhannesson G., Bjarnason O., Gonzales M. Reproductive factors and risk for breast cancer in Iceland. Int J Cancer. 1978 Jun 15;21(6):724–730. doi: 10.1002/ijc.2910210609. [DOI] [PubMed] [Google Scholar]

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