Skip to main content

Advertisement

SpringerLink
Log in

Basal-like subtype and BRCA1 dysfunction in breast cancers

  • Review Article
  • Published:
International Journal of Clinical Oncology Aims and scope Submit manuscript

Abstract

Basal-like breast cancers are characterized by their unique expression profile, with the frequent loss of BRCA1, caused by such mechanisms as promoter methylation and the overexpression of high-mobility group proteins of the A type 1 or inhibitor of differentiation 4. Clinicopathologically, basal-like cancers are estrogen receptor-, progesterone receptor-, and human epidermal growth factor receptor type 2 (HER2)-negative; they are of high grade and have a poor prognosis. The fundamental similarity between BRCA1-mutated and basal-like cancers indicates that disruption of BRCA1 may be an essential common initial pathogenic event. Furthermore, p53 mutation and EGFR overexpression occur similarly in BRCA1-mutated and basal-like cancers; these shared alterations provide very important information for understanding not only the genetic and epigenetic carcinogenic pathways in these tumors but also therapeutic strategies. Despite the limited available clinical data about response to chemotherapy, anthracycline-based chemotherapy seems to be effective in a distinct subset of basal-like cancers. Both disrupted BRCA1 and overexpressed topoisomerase II-α possibly found in basal-like cancers are speculated to be associated with their increased sensitivity to anthracyclines. If these tumors respond to this chemotherapy, a favorable prognosis might be expected; however, in patients who do not respond, the prognosis is poor. Currently, the sensitivity of basal-like cancers to taxanes is not clear, but considering that these tumors have disrupted mitotic checkpoint function, a poor response may be suggested. On the basis of in vitro studies, BRCA1-disrupted basal-like cancers may be sensitive to DNA-damaging agents including platinum-based compounds, topoisomerase I and II inhibitors, and alkylating agents. In future, new therapeutic approaches for patients with basal-like cancers that are unlikely to respond to chemotherapy should focus on molecules that are involved in the pathogenic pathways of this disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Perou CM, Sørlie T, Eisen MB, et al. (2000) Molecular portraits of human breast tumours. Nature 406:747–752

    Article  PubMed  CAS  Google Scholar 

  2. Sotiriou C, Neo SY, McShane LM, et al. (2003) Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A 100: 10393–10398

    Article  PubMed  CAS  Google Scholar 

  3. Turner NC, Reis-Filho JS (2006) Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25:5846–5853

    Article  PubMed  CAS  Google Scholar 

  4. Turner N, Tutt A, Ashworth A (2004) Hallmarks of “BRCAness” in sporadic cancers. Nat Rev Cancer 4:814–819

    Article  PubMed  CAS  Google Scholar 

  5. Yehiely F, Moyano JV, Evans JR, et al. (2006) Deconstructing the molecular portrait of basal-like breast cancer. Trends Mol Med 12:537–544

    Article  PubMed  CAS  Google Scholar 

  6. Reis-Filho JS, Tutt AN (2008) Triple negative tumours: a critical review. Histopathology 52:108–118

    Article  PubMed  CAS  Google Scholar 

  7. Nielsen TO, Hsu FD, Jensen K, et al. (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374

    Article  PubMed  CAS  Google Scholar 

  8. Banerjee S, Reis-Filho JS, Ashley S, et al. (2006) Basal-like breast carcinomas: clinical outcome and response to chemotherapy. J Clin Pathol 59:729–735

    Article  PubMed  CAS  Google Scholar 

  9. Foulkes WD, Brunet JS, Stefansson IM, et al. (2004) The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res 64:830–835

    Article  PubMed  CAS  Google Scholar 

  10. Vaziri SA, Krumroy LM, Elson P, et al. (2001) Breast tumor immunophenotype of BRCA1-mutation carriers is influenced by age at diagnosis. Clin Cancer Res 7:1937–1945

    PubMed  CAS  Google Scholar 

  11. Sorlie T, Tibshirani R, Parker J, et al. (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 100:8418–8423

    Article  PubMed  CAS  Google Scholar 

  12. Foulkes WD, Stefansson IM, Chappuis PO, et al. (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95:1482–1485

    PubMed  CAS  Google Scholar 

  13. Cleator S, Heller W, Coombes RC (2007) Triple-negative breast cancer: therapeutic options. Lancet Oncol 8:235–244

    Article  PubMed  Google Scholar 

  14. Catteau A, Harris WH, Xu CF, et al. (1999) Methylation of the BRCA1 promoter region in sporadic breast and ovarian cancer: correlation with disease characteristics. Oncogene 18:1957–1965

    Article  PubMed  CAS  Google Scholar 

  15. Baldassarre G, Battista S, Belletti B, et al. (2003) Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma. Mol Cell Biol 23:2225–2238

    Article  PubMed  CAS  Google Scholar 

  16. Turner NC, Reis-Filho JS, Russell AM, et al. (2007) BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 26: 2126–2132

    Article  PubMed  CAS  Google Scholar 

  17. Liu S, Ginestier C, Charafe-Jauffret E, et al. (2008) BRCA1 regulates human mammary stem/progenitor cell fate. Proc Natl Acad Sci U S A 105:1680–1685

    Article  PubMed  CAS  Google Scholar 

  18. Liu X, Holstege H, van der Gulden H, et al. (2007) Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci U S A 104:12111–12116

    Article  PubMed  CAS  Google Scholar 

  19. Kennedy RD, Quinn JE, Mullan PB, et al. (2004) The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst 96:1659–1668

    Article  PubMed  CAS  Google Scholar 

  20. Zdraveski ZZ, Mello JA, Marinus MG, et al. (2000) Multiple pathways of recombination define cellular responses to cisplatin. Chem Biol 7:39–50

    Article  PubMed  CAS  Google Scholar 

  21. Lafarge S, Sylvain V, Ferrara M, et al. (2001) Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway. Oncogene 20: 6597–6606

    Article  PubMed  CAS  Google Scholar 

  22. Fedier A, Steiner RA, Schwarz VA, et al. (2003) The effect of loss of Brca1 on the sensitivity to anticancer agents in p53-deficient cells. Int J Oncol 22:1169–1173

    PubMed  CAS  Google Scholar 

  23. Quinn JE, Kennedy RD, Mullan PB, et al. (2003) BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res 63:6221–6228

    PubMed  CAS  Google Scholar 

  24. Sylvain V, Lafarge S, Bignon YJ, et al. (2002) Dominant-negative activity of a Brca1 truncation mutant: effects on proliferation, tumorigenicity in vivo, and chemosensitivity in a mouse ovarian cancer cell line. Int J Oncol 20:845–853

    PubMed  CAS  Google Scholar 

  25. Delaloge SPP, Kloos I (2002) BRCA1-linked breast cancer (BC) is highly more chemosensitive than its BRCA2-linked or sporadic counterparts (abstract 120). Nice(France): Program and abstracts of the 27th Congress of the European Society for Medical Oncology 2002

  26. Goffin JR, Chappuis PO, Bégin LR, et al. (2003) Impact of germline BRCA1 mutations and overexpression of p53 on prognosis and response to treatment following breast carcinoma: 10-year follow up data. Cancer 97:527–536

    Article  PubMed  CAS  Google Scholar 

  27. Rouzier R, Perou CM, Symmans WF, et al. (2005) Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–585

    Article  PubMed  CAS  Google Scholar 

  28. Liedtke C, Mazouni C, Hess KR, et al. (2008) Response to neoadjuvant therapy and long-term survival in patients with triplenegative breast cancer. J Clin Oncol 26:1275–1281

    Article  PubMed  Google Scholar 

  29. Zhong Q, Chen CF, Li S, et al. (1999) Association of BRCA1 with the hRad50-hMre11-p95 complex and the DNA damage response. Science 285:747–750

    Article  PubMed  CAS  Google Scholar 

  30. Miyoshi Y, Kurosumi M, Kurebayashi J, et al. (2008) Topoisomerase II alpha-positive and BRCA1-negative phenotype: association with favorable response to epirubicin-based regimens for human breast cancers. Cancer Lett 264:44–53

    Article  PubMed  CAS  Google Scholar 

  31. Wang JC (1996) DNA topoisomerases. Annu Rev Biochem 65: 635–692

    Article  PubMed  CAS  Google Scholar 

  32. Cummings J, Smyth JF (1993) DNA topoisomerase I and II as targets for rational design of new anticancer drugs. Ann Oncol 4:533–543

    PubMed  CAS  Google Scholar 

  33. Tan DS, Marchió C, Jones RL, et al. (2008) Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat 111: 27–44

    Article  PubMed  CAS  Google Scholar 

  34. Carey LA, Dees EC, Sawyer L, et al. (2007) The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329–2334

    Article  PubMed  CAS  Google Scholar 

  35. Garcia P, Braguer D, Carles G, et al. (1994) Comparative effects of taxol and Taxotere on two different human carcinoma cell lines. Cancer Chemother Pharmacol 34:335–343

    Article  PubMed  CAS  Google Scholar 

  36. Diaz JF, Andreu JM (1993) Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: reversibility, ligand stoichiometry, and competition. Biochemistry 32:2747–2755

    Article  PubMed  CAS  Google Scholar 

  37. Quinn JE, Kennedy RD, Mullan PB, et al. (2003) BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis. Cancer Res 63:6221–6228

    PubMed  CAS  Google Scholar 

  38. Chabalier C, Lamare C, Racca C, et al. (2006) BRCA1 downregulation leads to premature inactivation of spindle checkpoint and confers paclitaxel resistance. Cell Cycle 5:1001–1007

    PubMed  CAS  Google Scholar 

  39. Xu X, Weaver Z, Linke SP, et al. (1999) Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3:389–395

    Article  PubMed  CAS  Google Scholar 

  40. Murata K, Sato T, Kanamaru R (1994) Effect of a new anticancer drug, docetaxel (RP56976), on human leukemia cell lines. Gan To Kagaku Ryoho 21:307–313

    PubMed  CAS  Google Scholar 

  41. Hata T, Furukawa T, Sunamura M, et al. (2005) RNA interference targeting aurora kinase A suppresses tumor growth and enhances the taxane chemosensitivity in human pancreatic cancer cells. Cancer Res 65:2899–2905

    Article  PubMed  CAS  Google Scholar 

  42. Byrski T, Gronwald J, Huzarski T, et al. (2008) Polish Hereditary Breast Cancer Consortium. Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat 108:289–296

    Article  PubMed  CAS  Google Scholar 

  43. Wysocki PJ, Korski K, Lamperska K, et al. (2008) Primary resistance to docetaxel-based chemotherapy in metastatic breast cancer patients correlates with a high frequency of BRCA1 mutations. Med Sci Monit 14:SC7–10

    PubMed  CAS  Google Scholar 

  44. Kurebayashi J, Yamamoto Y, Kurosumi M, et al. (2006) Loss of BRCA1 expression may predict shorter time-to-progression in metastatic breast cancer patients treated with taxanes. Anticancer Res 26:695–701

    PubMed  CAS  Google Scholar 

  45. Miyoshi Y, Kurosumi M, Kurebayashi J, et al. (2008) Low nuclear grade but not cell proliferation predictive of pathological complete response to docetaxel in human breast cancers. J Cancer Res Clin Oncol 134:561–567

    Article  PubMed  CAS  Google Scholar 

  46. Tong T, Zhong Y, Kong J, et al. (2004) Overexpression of Aurora-A contributes to malignant development of human esophageal squamous cell carcinoma. Clin Cancer Res 10:7304–7310

    Article  PubMed  CAS  Google Scholar 

  47. Jeng YM, Peng SY, Lin CY (2004) Overexpression and amplification of Aurora-A in hepatocellular carcinoma. Clin Cancer Res 10:2065–2071

    Article  PubMed  CAS  Google Scholar 

  48. Fraizer GC, Diaz MF, Lee IL, et al. (2004) Aurora-A/STK15/BTAK enhances chromosomal instability in bladder cancer cells. Int J Oncol 25:1631–1639

    PubMed  CAS  Google Scholar 

  49. Hu W, Kavanagh JJ, Deaver M, et al. (2005) Frequent overexpression of STK15/Aurora-A/BTAK and chromosomal instability in tumorigenic cell cultures derived from human ovarian cancer. Oncol Res 15:49–57

    PubMed  CAS  Google Scholar 

  50. Tatsuka M, Sato S, Kitajima S, et al. (2005) Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis. Oncogene 24:1122–1127

    Article  PubMed  CAS  Google Scholar 

  51. Mullan PB, Gorski JJ, Harkin DP (2006) BRCA1 — a good predictive marker of drug sensitivity in breast cancer treatment? Biochim Biophys Acta 1766:205–216

    PubMed  CAS  Google Scholar 

  52. Zdraveski ZZ, Mello JA, Marinus MG, et al. (2000) Multiple pathways of recombination define cellular responses to cisplatin. Chem Biol 7:39–50

    Article  PubMed  CAS  Google Scholar 

  53. Wood RD (1997) Nucleotide excision repair in mammalian cells. J Biol Chem 272:23465–23468

    Article  PubMed  CAS  Google Scholar 

  54. Moynahan ME, Cui TY, Jasin M (2001) Homology-directed DNA repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation. Cancer Res 61:4842–4850

    PubMed  CAS  Google Scholar 

  55. Farmer H, McCabe N, Lord CJ, et al. (2005) Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–921

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Breast and Endocrine Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Yasuo Miyoshi, Keiko Murase & Koushi Oh

Authors
  1. Yasuo Miyoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keiko Murase
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koushi Oh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuo Miyoshi.

About this article

Cite this article

Miyoshi, Y., Murase, K. & Oh, K. Basal-like subtype and BRCA1 dysfunction in breast cancers. Int J Clin Oncol 13, 395–400 (2008). https://doi.org/10.1007/s10147-008-0831-x

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10147-008-0831-x

Key words

Search

Navigation