Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Acta Medica Bulgarica

2 Issues per year

Open Access
Online
ISSN
0324-1750
See all formats and pricing
More options …

Molecular-Genetic Aspects of Breast Cancer

M. Krasteva
  • Corresponding author
  • Department of Molecular Genetics, Institute of Plant Physiology and Genetics, Bulgarian Academy of Sciences, Sofia, Bulgaria
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Sv Angelova
  • Department of Molecular Genetics, Institute of Plant Physiology and Genetics, Bulgarian Academy of Sciences, Sofia, Bulgaria
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Zl Gospodinova
  • Department of Molecular Genetics, Institute of Plant Physiology and Genetics, Bulgarian Academy of Sciences, Sofia, Bulgaria
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-02-06 | DOI: https://doi.org/10.1515/amb-2014-0024

Summary

Breast cancer is the most frequent malignancy among women. Advances in breast cancer knowledge have deciphered the involvement of a number of tumor suppressor genes and proto-oncogenes in disease pathogenesis. These genes are part of the complex biochemical pathways, which enable cell cycle control and maintenance of genome integrity. Their function may be disrupted as a result of alterations in gene sequence or misregulation of gene expression including alterations in DNA methylation pattern. The present review summarizes the main findings on major breast cancer related genes BRCA1/2, p53, ATM, CHEK2, HER2, PIK3CA and their tumorigenic inactivation/activation. The potential clinical importance of these genes with respect to patients’ prognosis and therapy are also discussed. The possible implication of other putative breast cancer related genes is also outlined. The first elaborate data on the genetic and epigenetic status of the above mentioned genes concerning Bulgarian patients with the sporadic form of the disease are presented. The studies indicate for a characteristic mutational spectrum in some of the genes for the Bulgarian patients and specific correlation between the status of different genes and clinicopathological characteristics.

Keywords : breast cancer; tumor suppressor genes; proto-oncogenes; mutations; DNA hypermethylation; clinical impact

References

  • 1. Ahn, J. Y. et al. Threonine 68 phosphorylation by ataxia telangiectasia mutated is required for efficient activation of Chk2 in response to ionizing radiation. - Cancer Res., 60, 2000, № 21, 5934-5936.Google Scholar

  • 2. Ai, L. et al. Ataxia-telangiectasia-mutated (ATM) gene in head and neck squamous cell carcinoma: promoter hypermethylation with clinical correlation in 100 cases. - Cancer Epidemiol. Biomarkers Prev., 13, 2004, № 1, 150-156.Google Scholar

  • 3. Albain, K. S. et al. HER2 overexpression in Breast Cancer. - Genetech Inc., 1998.Google Scholar

  • 4. Allinen, M. et al. Mutation analysis of the CHK2 gene in families with hereditary breast cancer. - Br. J. Cancer, 85, 2001, № 2, 209-212.Google Scholar

  • 5. Almond, N. et V. Rotter. Involvement of p53 in cell differentiation and development. - Biochim. Biophys. Acta /Reviews on Cancer, 1333, 1997, № 1, 1-27.Google Scholar

  • 6. Angele, S. et al. Abnormal expression of the ATM and TP53 genes in sporadic breast carcinomas. - Clin. Cancer Res., 6, 2000, 3536-3544.Google Scholar

  • 7. Angelova, S. G. et al. CHEK2 gene alterations independently increase the risk of death from breast cancer in Bulgarian patients. - Neoplasma, 59, 2012, № 6, 622-630.CrossrefGoogle Scholar

  • 8. Bell, D. W. et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science, 286, 1999, № 5449, 2528-2531.Google Scholar

  • 9. Bernstein, J. L. et al. ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer. - Br. J. Cancer, 89, 2003, 1513-1516.Google Scholar

  • 10. Bogdanova, N. et al. Association of two mutations in the CHEK2 gene with breast cancer. - Int. J. Cancer, 116, 2005, № 2, 263-266.Google Scholar

  • 11. Børresen, A. L. et al. Breast cancer and other cancers in Norwegian families with ataxia-telangiectasia. - Genes Chromosomes Cancer, 2, 1990, № 4, 339-340.PubMedCrossrefGoogle Scholar

  • 12. Bozhanov, S. / Angelova S. et al. Alterations in p53, BRCA1, ATM, PIK3CA, and HER2 genes and their effect in modifying clinicopathological characteristics and overall survival of Bulgarian patients with breast cancer. -J. Cancer Res. Clin. Oncol., 136, 2010, 1657-1669.Google Scholar

  • 13. Brose, M. S. et al. Cancer Risk Estimates for BRCA1 Mutation Carriers Identified in a Risk Evaluation Program. - J. Natl. Cancer Inst., 94, 2002, 1365-1372.CrossrefGoogle Scholar

  • 14. Cable, P. L. et al. Novel consensus DNA-binding sequence for BRCA1 protein complexes. - Mol. Carcinog., 38, 2003, № 2, 85-96.CrossrefGoogle Scholar

  • 15. Campbell, l. G. et al. Mutation of the PIK3CA gene in ovarian and breast cancer. - Cancer Res., 64, 2004, 7678-7681.CrossrefGoogle Scholar

  • 16. Carr, J. A. et al. The association of HER-2/neu ampliffication with breast cancer recurrence. - Arch. Surg., 135, 2000, 1469-1474.Google Scholar

  • 17. Chen, S. et al. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. - J. Clin. Oncol., 24, 2006, № 6, 863-871.CrossrefGoogle Scholar

  • 18. Cybulski, C. et al. A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. - Breast Cancer Res. Treat., 102, 2007, № 1, 119-122.Google Scholar

  • 19. de Jong, M. M. et al. Genes other than BRCA1and BRCA2 involved in breast cancer susceptibility. - J. Med. Genet., 39, 2002, 225-242.CrossrefGoogle Scholar

  • 20. Dobrovic, A. et D. Simpfendorfer. Methylation of the BRCA1 Gene in Sporadic Breast Cancer. - Cancer Res., 57, 1997, 3347-3350.Google Scholar

  • 21. Honrado, E. et al. Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations. - Oncogene, 25, 2006, № 43, 5837-5845.CrossrefGoogle Scholar

  • 22. Iannuzzi, C. M. et al. ATM mutations in female breast cancer patients predict for an increase in radiation-induced late effects. - Int. J. Radiat. Oncol. Biol. Phys., 52, 2002, № 3, 606-613.CrossrefPubMedGoogle Scholar

  • 23. Kastan, M. B. et J. Bartek. Cell-cycle checkpoints and cancer. - Nature, 432, 2004, № 7015, 316-323.Google Scholar

  • 24. Kilinc, N. et M. Yaldiz. P53, c-erbB-2 expression and steroid hormone receptors in breast carcinoma: correlations with histopathological parameters. - Eur. J. Gynaecol. Oncol., 25, 2004, 5, 606-610.Google Scholar

  • 25. Kilpivaara, O. et al. CHEK2 variant I157T may be associated with increased breast cancer risk. - Int. J. Cancer, 111, 2004, 543-547.Google Scholar

  • 26. Krasteva, M. E. et al. Breast cancer patients with hypermethylation in the promoter of BRCA1 gene exhibit favorable clinical status. - Neoplasma, 59, 2012, № 1, 85-91.Google Scholar

  • 27. Krasteva, M. et al. Aberrant promoter methylation in p53 and ATM genes was not associated with sporadic breast carcinogenesis in Bulgarian patients. - J. BioSci. Biotech., 3, 2014, № 2, 105-109.Google Scholar

  • 28. Lacroix, M., R. A. Toillon et G. Leclercq. P53 and breast cancer, an update. - Endocr. Relat. Cancer, 13, 2006, № 2, 293-325.CrossrefGoogle Scholar

  • 29. Lavin, M. F. et S. Kozlov. ATM activation and DNA damage response. - Cell Cycle, 6, 2007, № 8, 931-942.CrossrefGoogle Scholar

  • 30. Lavin, M. F. The Mre11 complex and ATM: a two-way functional interaction in recognising and signaling DNA double strand breaks. - DNA Repair (Amst), 3, 2004, № 11, 1515-1520.CrossrefGoogle Scholar

  • 31. Lawler, J. et al. Thrombospondin-1 gene expression affects survival and tumor spectrum of p53- deficient mice. - Am. J. Pathol., 159, 2001, 1949-1956.Google Scholar

  • 32. Li, S. et al. Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. - Nature, 406, 2000, № 6792, 210-215.Google Scholar

  • 33. Lukas, C. et al. DNA damage-activated kinase Chk2 is independent of proliferation or differentiation yet correlates with tissue biology. - Cancer Res., 61, 2001, № 13, 4990-4993.Google Scholar

  • 34. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. - Science, 250, 1990, № 4985, 1233-1238.Google Scholar

  • 35. Matsuoka, S. et al. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. - Proc. Natl. Acad. Sci. U S A, 97, 2000, № 19, 10389-10394.CrossrefGoogle Scholar

  • 36. Meijers-HeIjboer, H. et al. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. - Nat. Genet., 31, 2002, № 1, 55-59.Google Scholar

  • 37. Muthuswamy, S. K. et al. ErbB2, but not ErbB1, reinitiates proliferation and induces luminal repopulation in epithelial acini. - Nat. Cell Biol., 3, 2001, 785-792.CrossrefPubMedGoogle Scholar

  • 38. Offterdinger, M., S. M. Schneider et T. W. Grunt. Heregulin and retinoids synergistically induce branching morphogenesis of breast cancer cells cultivated in 3D collagen gels. - J. Cell Physiol., 195, 2003, 260-275.Google Scholar

  • 39. Olivier, M. et al. The IARC TP53 database: new online mutation analysis and recommendations to users. - Hum. Mutat., 19, 2002, 607-614.CrossrefGoogle Scholar

  • 40. O’ DrIscoll M. et P. A. Jeggo. The role of double-strand break repair - insights from human genetics. - Nat. Rev. Genet., 7, 2006, № 1, 45-54.Google Scholar

  • 41. Peto, J. et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. - J. Natl. Cancer Inst., 91, 1999, № 11, 943-949.CrossrefGoogle Scholar

  • 42. Pharoah, P. D., N. E. Day et C. Caldas. Somatic mutations in the p53 gene and prognosis in breast cancer: a meta-analysis. - Br. J. Cancer, 80, 1999, 1968-1973.Google Scholar

  • 43. Rice, J. C., K. S. Massey-Brown et B. W. Futscher. Aberrant methylation of the BRCA1 CpG island promoter is associated with decreased BRCA1 mRNA in sporadic breast cancer cells. - Oncogene, 17, 1998, 1807-1812.CrossrefGoogle Scholar

  • 44. Ross, J. S. et al. The Her-2/neu gene and protein in breast cancer: biomarker and target of therapy. - Oncologist, 8, 2003, 307-325.CrossrefGoogle Scholar

  • 45. Rudolph, P. et al. Correlation between p53, c-erbB-2, and topoisomerase II alpha expression, DNA ploidy, hormonal receptor status and proliferation in 356 node-negative breast carcinomas: prognostic implications. - J. Pathol., 187, 1999, 207-216.Google Scholar

  • 46. Saal, L. H. et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. - Cancer Res., 65, 2005, 2554-2559.CrossrefGoogle Scholar

  • 47. Sansal, I. et W. R. Sellers. The biology and clinical relevance of the PTEN tumor suppressor pathway. - J. Clin. Oncol., 22, 2004, 2954-2963.CrossrefGoogle Scholar

  • 48. Seo, Y. R. et H. J. Jung. The potential roles of p53 tumor suppressor in nucleotide excision repair (NER) and base excision repair (BER). - Exp. Mol. Med., 36, 2004, № 60, 505-509.CrossrefGoogle Scholar

  • 49. Shaag, A. et al. Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. - Hum. Mol. Genet., 14, 2005, № 4, 555-563.Google Scholar

  • 50. Singh, B. et al. p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas. - Genes Dev., 16, 2002, 984-993.Google Scholar

  • 51. Slamon, D. J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. - Science, 235, 1987, 177-182.Google Scholar

  • 52. Sodha, N. et al. Screening hCHK2 for mutations. - Science, 289, 2000, № 5478, 359.Google Scholar

  • 53. Stoppa - Lyonnet, D. et al. Familial invasive breast cancers: worse outcome related to BRCA1 mutations. - J. Clin. Oncol., 18, 2000, 4053-4059.Google Scholar

  • 54. Tuma, R. S. Trastuzumab trials steal show at ASCO meeting. - J. Natl. Cancer Inst., 97, 2005, 870-871.CrossrefGoogle Scholar

  • 55. Turner, N., A. Tutt et A. Ashworth. Hallmarks of ‚BRCAness‘ in sporadic cancers. - Nature Reviews of Cancer, 4, 2004, 814-819.PubMedGoogle Scholar

  • 56. Weischer, M. et al. Increased risk of breast cancer associated with CHEK2*1100delC. - J. Clin. Oncol., 25, 2007, № 1, 57-63.Google Scholar

  • 57. Wong, M. W. et al. BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. - Breast Cancer Res. Treat., 127, 2011, № 3, 853-859.CrossrefGoogle Scholar

  • 58. Xu, X., L. M. Tsvetkov et D. F. Stern. Chk2 activation and phosphorylation-dependent oligomerization. - Mol. Cell Biol., 22, 2002, № 12, 4419-4432. CrossrefGoogle Scholar

About the article

Published Online: 2015-02-06

Published in Print: 2014-12-01


Citation Information: Acta Medica Bulgarica, ISSN (Online) 0324-1750, DOI: https://doi.org/10.1515/amb-2014-0024.

Export Citation

© 2015. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

Comments (0)

Please log in or register to comment.
Log in