Skip to main content

Advertisement

SpringerLink
Log in

Molecular insights on basal-like breast cancer

  • Review
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Molecular classification of breast cancer (BC) identified diverse subgroups that encompass distinct biological behavior and clinical implications, in particular in relation to prognosis, spread, and incidence of recurrence. Basal-like breast cancers (BLBC) compose up to 15% of BC and are characterized by lack of estrogen receptor (ER), progesterone receptor (PR), and HER-2 amplification with expression of basal cytokeratins 5/6, 14, 17, epidermal growth factor receptor (EGFR), and/or c-KIT. There is an overlap in definition between triple-negative BC and BLBC due to the triple-negative profile of BLBC. Also, most BRCA1-associated BCs are BLBC, triple negative, and express basal cytokeratins (5/6, 14, 17) and EGFR. There is a link between sporadic BLBC (occurring in women without germline BRCA1 mutations) with dysfunction of the BRCA1 pathway. Despite the molecular and clinical similarities, these subtypes respond differently to neoadjuvant therapy. BLBCs are associated with an aggressive phenotype, high histological grade, poor clinical behavior, and high rates of recurrences and/or metastasis. Their molecular features render these tumors especially refractory to anti-hormonal-based therapies and the overall prognosis of this subset remains poor. In this article, the molecular profile, genomic, and epigenetic characteristics as well as BRCA1 pathway dysfunction, clinicopathological behavior, and therapeutic options in BLBC are presented, with emphasis on the discordant findings in current literature.

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

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Haupt B, Ro JY, Schwartz MR (2010) Basal-like breast carcinoma: a phenotypically distinct entity. Arch Pathol Lab Med 134:130–133

    PubMed  Google Scholar 

  2. Rakha EA, El-Sayed ME, Green AR et al (2007) Prognostic markers in triple-negative breast cancer. Cancer 109:25–32

    Article  PubMed  CAS  Google Scholar 

  3. Presson AP, Yoon NK, Bagryanova L et al (2011) Protein expression based multimarker analysis of breast cancer samples. BMC Cancer. doi:10.1186/1471-2407-11-230

  4. Weigelt B, Reis-Filho JS (2010) Molecular profiling currently offers no more than tumour morphology and basic immunohistochemistry. Breast Cancer Res. doi:10.1186/BCR2734

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

    Article  PubMed  CAS  Google Scholar 

  6. Yehiely F, Moyano JV, Evans JR et al (2006) Deconstructing the molecular portrait of basal-like breast cancer. Trends Mol Med 12(11):537–544

    Article  PubMed  CAS  Google Scholar 

  7. Sørlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874

    Article  PubMed  Google Scholar 

  8. Niemeier LA, Dabbs DJ, Beriwal S et al (2010) Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod Pathol 23:205–212

    Article  PubMed  CAS  Google Scholar 

  9. Irvin WJ Jr, Carey LA (2008) What is triple-negative breast cancer? Eur J Cancer 44:2799–2805

    Article  PubMed  CAS  Google Scholar 

  10. Rakha EA, Elsheikh SE, Aleskandarany MA et al (2009) Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes. Clin Cancer Res 15:2302–2310

    Article  PubMed  CAS  Google Scholar 

  11. Schneider BP, Winer EP, Foulkes WD et al (2008) Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res 14:8010–8018 Review

    Article  PubMed  CAS  Google Scholar 

  12. Gastaldi S, Comoglio PM, Trusolino L (2010) The Met oncogene and basal-like breast cancer: another culprit to watch out for? Breast Cancer Res. doi:10.1186/BCR2617

  13. Herschkowitz JI, Simin K, Weigman VJ et al (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol. doi: 10.1186/gb-2007-8-5-r76

  14. Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K et al (2009) Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res 69:4116–4124

    Article  PubMed  CAS  Google Scholar 

  15. Prat A, Parker JS, Karginova O et al (2010) Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. doi:10.1186/BCR2635

  16. Herschkowitz JI, Zhao W, Zhang M et al (2011) Breast cancer special feature: comparative oncogenomics identifies breast tumors enriched in functional tumor-initiating cells. Proc Natl Acad Sci USA. doi:10.1073/pnas.1018862108

  17. Farmer P, Bonnefoi H, Becette V et al (2005) Identification of molecular apocrine breast tumours by microarray analysis. Oncogene 24:4660–4671

    Article  PubMed  CAS  Google Scholar 

  18. Lopez-Garcia MA, Geyer FC, Lacroix-Triki M et al (2010) Breast cancer precursors revisited: molecular features and progression pathways. Histopathology 57:171–192

    Article  PubMed  Google Scholar 

  19. 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 

  20. 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 USA 100:8418–8423

    Article  PubMed  CAS  Google Scholar 

  21. Böcker W, Bier B, Freytag G et al (1992) An immunohistochemical study of the breast using antibodies to basal and luminal keratins, alpha-smooth muscle actin, vimentin, collagen IV and laminin. Part I: normal breast and benign proliferative lesions. Virchows Arch A Pathol Anat Histopathol 421:315–322

    Article  PubMed  Google Scholar 

  22. Korsching E, Packeisen J, Agelopoulos K et al (2002) Cytogenetic alterations and cytokeratin expression patterns in breast cancer: integrating a new model of breast differentiation into cytogenetic pathways of breast carcinogenesis. Lab Investig 82:1525–1533

    PubMed  CAS  Google Scholar 

  23. Choo JR, Nielsen TO (2010) Biomarkers for basal-like breast cancer. Cancers 2:1040–1065

    Article  CAS  Google Scholar 

  24. Khramtsov AI, Khramtsova GF, Tretiakova M et al (2010) Wnt/beta-catenin pathway activation is enriched in basal-like breast cancers and predicts poor outcome. Am J Pathol 176:2911–2920

    Article  PubMed  Google Scholar 

  25. Turashvili G, Bouchal J, Burkadze G et al (2006) Wnt signaling pathway in mammary gland development and carcinogenesis. Pathobiology 73:213–223

    Article  PubMed  CAS  Google Scholar 

  26. Rubovszky G, Udvarhelyi N, Horváth Z et al (2010) Triple-negative breast carcinoma—review of current literature. Magy Onkol 54:325–335 Review

    Article  PubMed  Google Scholar 

  27. Honeth G, Bendahl PO, Ringnér M et al (2008) The CD44+/CD24− phenotype is enriched in basal-like breast tumors. Breast Cancer Res. doi:10.1186/BCR2108

  28. Rakha EA, Reis-Filho JS, Ellis IO (2008) Basal-like breast cancer: a critical review. J Clin Oncol 26:2568–2581 Review

    Article  PubMed  Google Scholar 

  29. Kwei KA, Kung Y, Salari K et al (2010) Genomic instability in breast cancer: pathogenesis and clinical implications. Mol Oncol 4:255–256

    Article  PubMed  CAS  Google Scholar 

  30. Bergamaschi A, Kim YH, Wang P et al (2006) Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer. Genes Chromosomes Cancer 45:1033–1040

    Article  PubMed  CAS  Google Scholar 

  31. Toft DJ, Cryns VL (2011) Minireview: basal-like breast cancer: from molecular profiles to targeted therapies. Mol Endocrinol 25:199–211 Review

    Article  PubMed  CAS  Google Scholar 

  32. Letessier A, Sircoulomb F, Ginestier C et al (2006) Frequency, prognostic impact, and subtype association of 8p12, 8q24, 11q13, 12p13, 17q12, and 20q13 amplifications in breast cancers. BMC Cancer. doi:10.1186/1471-2407-6-245

  33. Adélaïde J, Finetti P, Bekhouche I et al (2007) Integrated profiling of basal and luminal breast cancers. Cancer Res 67:11565–11575

    Article  PubMed  Google Scholar 

  34. Wang ZC, Lin M, Wei LJ et al (2004) Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers. Cancer Res 64:64–71

    Article  PubMed  CAS  Google Scholar 

  35. Liu F, Chen X, Allali-Hassan A et al (2009) Discovery of a 2, 4-diamino-7-aminoalkoxyquinazoline as a potent and selective inhibitor of histone lysine methyltransferase G9a. J Med Chem 52:7950–7953

    Article  PubMed  CAS  Google Scholar 

  36. Roll JD, Rivenbark AG, Jones WD et al (2008) DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines. Mol Cancer. doi:10.1186/1476-4598-7-15

  37. Parrella P, Poeta ML, Gallo AP et al (2004) Nonrandom distribution of aberrant promoter methylation of cancer-related genes in sporadic breast tumors. Clin Cancer Res 10:5349–5354

    Article  PubMed  CAS  Google Scholar 

  38. Li S, Rong M, Iacopetta B (2006) DNA hypermethylation in breast cancer and its association with clinicopathological features. Cancer Lett 237:272–280

    Article  PubMed  CAS  Google Scholar 

  39. Holm K, Hegardt C, Staaf J et al (2010) Molecular subtypes of breast cancer are associated with characteristic DNA methylation patterns. Breast Cancer Res. doi:10.1186/BCR2590

  40. Bae YK, Brown A, Garrett E et al (2004) Hypermethylation in histologically distinct classes of breast cancer. Clin Cancer Res 10:5998–6005

    Article  PubMed  CAS  Google Scholar 

  41. Dumont N, Wilson MB, Crawford YG et al (2008) Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc Natl Acad Sci USA 105:14867–14872

    Article  PubMed  CAS  Google Scholar 

  42. Elsheikh SE, Green AR, Rakha EA et al (2009) Global histone modifications in breast cancer correlate with tumor phenotypes, prognostic factors, and patient outcome. Cancer Res 69:3802–3809

    Article  PubMed  CAS  Google Scholar 

  43. Van’t Veer LJ, Dai H, van de Vijver MJ et al (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536

    Article  Google Scholar 

  44. Waddell N, Arnold J, Cocciardi S et al (2010) Subtypes of familial breast tumours revealed by expression and copy number profiling. Breast Cancer Res Treat 123:661–677

    Article  PubMed  Google Scholar 

  45. Hedenfalk I, Ringner M, Ben-Dor A et al (2003) Molecular classification of familial non-BRCA1/BRCA2 breast cancer. Proc Natl Acad Sci USA 100:2532–2537

    Article  PubMed  CAS  Google Scholar 

  46. Sørlie T (2004) Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer 40:2667–2675 Review

    Article  PubMed  Google Scholar 

  47. Rakha EA, Reis-Filho JS, Ellis IO (2008) Impact of basal-like breast carcinoma determination for a more specific therapy. Pathobiology 75:95–103

    Article  PubMed  Google Scholar 

  48. Gorski JJ, Kennedy RD, Hosey AM et al (2009) The complex relationship between BRCA1 and ERalpha in hereditary breast cancer. Clin Cancer Res 15:1514–1518

    Article  PubMed  CAS  Google Scholar 

  49. Ray PS, Wang J, Qu Y et al (2010) FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Res 70:3870–3876

    Article  PubMed  CAS  Google Scholar 

  50. Yamamoto Y, Iwase H (2010) Clinicopathological features and treatment strategy for triple-negative breast cancer. Int J Clin Oncol 15(4):341–351

    Article  PubMed  Google Scholar 

  51. Kobayashi S (2008) Basal-like subtype of breast cancer: a review of its unique characteristics and their clinical significance. Breast Cancer 15:153–158

    Article  PubMed  Google Scholar 

  52. Millikan RC, Newman B, Tse CK, Moorman PG et al (2008) Epidemiology of basal-like breast cancer. Breast Cancer Res Treat 109:123–139

    Article  PubMed  Google Scholar 

  53. Fong PC, Boss DS, Yap TA et al (2009) Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 361:123–134

    Article  PubMed  CAS  Google Scholar 

  54. Ismail-Khan R, Bui MM (2010) A review of triple-negative breast cancer. Cancer Control 17:173–176

    PubMed  Google Scholar 

  55. Dong Y, Li A, Wang J et al (2010) Synthetic lethality through combined Notch-epidermal growth factor receptor pathway inhibition in basal-like breast cancer. Cancer Res 70:5465–5474

    Article  PubMed  CAS  Google Scholar 

  56. Rodríguez-Pinilla SM, Sarrió D, Honrado E et al (2007) Vimentin and laminin expression is associated with basal-like phenotype in both sporadic and BRCA1-associated breast carcinomas. J Clin Pathol 60:1006–1012

    Article  PubMed  Google Scholar 

  57. Rodríguez-Pinilla SM, Sarrió D, Honrado E et al (2006) Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin Cancer Res 12:1533–1539

    Article  PubMed  Google Scholar 

  58. Li H, Cherukuri P, Li N et al (2007) Nestin is expressed in the basal/myoepithelial layer of the mammary gland and is a selective marker of basal epithelial breast tumors. Cancer Res 67:501–510

    Article  PubMed  CAS  Google Scholar 

  59. Parry S, Savage K, Marchiò C et al (2008) Nestin is expressed in basal-like and triple negative breast cancers. J Clin Pathol 61:1045–1050

    Article  PubMed  CAS  Google Scholar 

  60. Charafe-Jauffret E, Monville F, Bertucci F et al (2007) Moesin expression is a marker of basal breast carcinomas. Int J Cancer 121:1779–1785

    Article  PubMed  CAS  Google Scholar 

  61. Elsheikh SE, Green AR, Rakha EA et al (2008) Caveolin 1 and Caveolin 2 are associated with breast cancer basal-like and triple-negative immunophenotype. Br J Cancer 99:327–334

    Article  PubMed  CAS  Google Scholar 

  62. Pinilla SM, Honrado E, Hardisson D et al (2006) Caveolin-1 expression is associated with a basal-like phenotype in sporadic and hereditary breast cancer. Breast Cancer Res Treat 99:85–90

    Article  PubMed  CAS  Google Scholar 

  63. Savage K, Lambros MB, Robertson D et al (2007) Caveolin 1 is overexpressed and basal-like and metaplastic breast carcinomas: a morphologic, ultrastructural, amplified in a subset of immunohistochemical, and in situ hybridization analysis. Clin Cancer Res 13:90–101

    Article  PubMed  CAS  Google Scholar 

  64. Savage K, Leung S, Todd SK et al (2008) Distribution and significance of caveolin 2 expression in normal breast and invasive breast cancer: an immunofluorescence and immunohistochemical analysis. Breast Cancer Res Treat 110:245–256

    Article  PubMed  CAS  Google Scholar 

  65. Lu S, Simin K, Khan A et al (2008) Analysis of integrin beta4 expression in human breast cancer: association with basal-like tumors and prognostic significance. Clin Cancer Res 14:1050–1058

    Article  PubMed  CAS  Google Scholar 

  66. Reis-Filho JS, Steele D, Di Palma S et al (2006) Distribution and significance of nerve growth factor receptor (NGFR/p75NTR) in normal, benign and malignant breast tissue. Mod Pathol 19:307–319

    Article  PubMed  CAS  Google Scholar 

  67. Hasegawa M, Moritani S, Murakumo Y et al (2008) CD109 expression in basal-like breast carcinoma. Pathol Int 58:288–294

    Article  PubMed  Google Scholar 

  68. Matos I, Dufloth R, Alvarenga M et al (2005) p63, cytokeratin 5, and P-cadherin: three molecular markers to distinguish basal phenotype in breast carcinomas. Virchows Arch 447:688–694

    Article  PubMed  CAS  Google Scholar 

  69. Paredes J, Lopes N, Milanezi F et al (2007) P-cadherin and cytokeratin 5: useful adjunct markers to distinguish basal-like ductal carcinomas in situ. Virchows Arch 450:73–80

    Article  PubMed  CAS  Google Scholar 

  70. Zabouo G, Imbert AM, Jacquemier J et al (2009) CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines. Breast Cancer Res 11:R1

    Article  PubMed  Google Scholar 

  71. Klingbeil P, Natrajan R, Everitt G et al (2010) CD44 is overexpressed in basal-like breast cancers but is not a driver of 11p13 amplification. Breast Cancer Res Treat 120:95–109

    Article  PubMed  CAS  Google Scholar 

  72. Viale G, Rotmensz N, Maisonneuve P et al (2009) Invasive ductal carcinoma of the breast with the “triple-negative” phenotype: prognostic implications of EGFR immunoreactivity. Breast Cancer Res Treat 116:317–328

    Article  PubMed  CAS  Google Scholar 

  73. Mani SA, Yang J, Brooks M et al (2007) Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci USA 104:10069–10074

    Article  PubMed  CAS  Google Scholar 

  74. Umemura S, Shirane M, Takekoshi S et al (2009) Overexpression of E2F-5 correlates with a pathological basal phenotype and a worse clinical outcome. Br J Cancer 100:764–771

    Article  PubMed  CAS  Google Scholar 

  75. Ribeiro-Silva A, Ramalho LN, Garcia SB et al (2005) p63 correlates with both BRCA1 and cytokeratin 5 in invasive breast carcinomas: further evidence for the pathogenesis of the basal phenotype of breast cancer. Histopathology 47:458–466

    Article  PubMed  CAS  Google Scholar 

  76. Rakha EA, Putti TC, Abd El-Rehim DM et al (2006) Morphological and immunophenotypic analysis of breast carcinomas with basal and myoepithelial differentiation. J Pathol 208:495–506

    Article  PubMed  CAS  Google Scholar 

  77. Herschkowitz JI, He X, Fan C et al (2008) The functional loss of the retinoblastoma tumour suppressor is a common event in basal-like and luminal B breast carcinomas. Breast Cancer Res 10(5):R75

    Article  PubMed  Google Scholar 

  78. Kuroda H, Ishida F, Nakai M et al (2008) Basal cytokeratin expression in relation to biological factors in breast cancer. Hum Pathol 39:1744–1750

    Article  PubMed  CAS  Google Scholar 

  79. Walter O, Prasad M, Lu S et al (2009) IMP3 is a novel biomarker for triple negative invasive mammary carcinoma associated with a more aggressive phenotype. Hum Pathol 40:1528–1533

    Article  PubMed  CAS  Google Scholar 

  80. Skaland I, Janssen EA, Gudlaugsson E et al (2009) The prognostic value of the proliferation marker phosphohistone H3 (PPH3) in luminal, basal-like and triple negative phenotype invasive lymph node-negative breast cancer. Cell Oncol 31:261–271

    PubMed  CAS  Google Scholar 

  81. Zhang H, Rakha EA, Ball GR et al (2010) The proteins FABP7 and OATP2 are associated with the basal phenotype and patient outcome in human breast cancer. Breast Cancer Res Treat 121:41–51

    Article  PubMed  CAS  Google Scholar 

  82. Tang XY, Umemura S, Tsukamoto H et al (2010) Overexpression of fatty acid binding protein-7 correlates with basal-like subtype of breast cancer. Pathol Res Pract 206:98–101

    Article  PubMed  CAS  Google Scholar 

  83. Moyano JV, Evans JR, Chen F et al (2006) AlphaB-crystallin is a novel oncoprotein that predicts poor clinical outcome in breast cancer. J Clin Invest 116:261–270

    Article  PubMed  CAS  Google Scholar 

  84. Sitterding SM, Wiseman WR, Schiller CL et al (2008) AlphaB-crystallin: a novel marker of invasive basal-like and metaplastic breast carcinomas. Ann Diagn Pathol 12:33–40

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank the regional counsel of Auvergne and Ligue Nationale contre le Cancer (Allier Committee).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Oncology, Lund University, BMC C.13, Klinikgatan 28, 221 84, Lund, Sweden

    Mev Dominguez Valentin

  2. Department of Medicine and Oncology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada

    Sabrina Daniela da Silva & Moulay Alaoui-Jamali

  3. Department of Oncogenetics, Centre Jean Perrin, Clermont-Ferrand, France

    Maud Privat & Yves-Jean Bignon

  4. Clermont Université, EA4233, Clermont-Ferrand, France

    Yves-Jean Bignon

Authors
  1. Mev Dominguez Valentin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabrina Daniela da Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maud Privat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Moulay Alaoui-Jamali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yves-Jean Bignon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mev Dominguez Valentin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Valentin, M.D., da Silva, S.D., Privat, M. et al. Molecular insights on basal-like breast cancer. Breast Cancer Res Treat 134, 21–30 (2012). https://doi.org/10.1007/s10549-011-1934-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1934-z

Keywords

Search

Navigation