Quadruple negative breast cancer

  • Meiling Huang
  • Jiang Wu
  • Rui LingEmail author
  • Nanlin LiEmail author
Review Article


Quadruple negative breast cancer (QNBC), lacking the expression of ER (estrogen receptor), PR (progesterone receptor), HER2 (human epidermal growth factor receptor-2) and AR (androgen receptor), was regarded as one breast cancer subtype with the worst prognosis. Recently, the molecular features of QNBC are not well understood. Different from AR-positive triple-negative breast cancer, QNBC is insensitive to conventional chemotherapeutic agents and has no efficient treatment targets. However, QNBC has been shown to express unique proteins that may be amenable to use in the development of targeted therapies. Here we reviewed the features of QNBC and proteins that may serve as effective targets for QNBC treatment, such as ACSL4, SKP2, immune checkpoint inhibitors, EGFR, MicroRNA signatures and Engrailed 1.


Quadruple negative breast cancer (QNBC) Clinical features Biomarkers 



This study was funded by The National Science Foundation of China [No. 81572917 and No. 81472598] and Wujieping Foundation [No. 320.6750.13292].

Compliance with ethical standards

Conflict of interest

The authors declare that we have no conflict of interest.

Ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

This article does not contain any studies with human participants.


  1. 1.
    Ali AM, Ansari JAK, El-Aziz NMA, Abozeed WN, Warith AMA, Alsaleh K, Nabholtz JM. Triple negative breast cancer: a tale of two decades. Anticancer Agents Med Chem. 2017;17(4):491–9. Scholar
  2. 2.
    Garrido-Castro AC, Lin NU, Polyak K. Insights into molecular classifications of triple-negative breast cancer: improving patient selection for treatment. Cancer Discov. 2019;9(2):176–98. Scholar
  3. 3.
    Jhan JR, Andrechek ER. Triple-negative breast cancer and the potential for targeted therapy. Pharmacogenomics. 2017;18(17):1595–609. Scholar
  4. 4.
    Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA. Acute myocardial infarction as the presenting symptom of acute myeloblastic leukemia with extreme hyperleukocytosis. American Journal of Hematology. 2002;712750–67. Scholar
  5. 5.
    Mayer IA, Abramson VG, Lehmann BD, Pietenpol JA. New strategies for triple-negative breast cancer—deciphering the heterogeneity. Clin Cancer. 2014;20(4):782–90. Scholar
  6. 6.
    Hon JD, Singh B, Sahin A, Du G, Wang J, Wang VY, Deng FM, Zhang DY, Monaco ME, Lee P. Breast cancer molecular subtypes: from TNBC to QNBC. Am J Cancer Res. 2016;6(9):1864–72.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Gucalp A, Traina TA. Targeting the androgen receptor in triple-negative breast cancer. PLoS Med. 2016;40(2–4):141–50. Scholar
  8. 8.
    Collins LC, Cole KS, Marotti JD, Hu R, Schnitt SJ, Tamimi RM. Androgen receptor expression in breast cancer in relation to molecular phenotype: results from the Nurses’ Health Study. Mod Pathol. 2011;24(7):924–31. Scholar
  9. 9.
    Tsutsumi Y. Apocrine carcinoma as triple-negative breast cancer: novel definition of apocrine-type carcinoma as estrogen/progesterone receptor-negative and androgen receptor-positive invasive ductal carcinoma. Jpn J Clin Oncol. 2012;42(5):375–86. Scholar
  10. 10.
    Barton VN, D'Amato NC, Gordon MA, Lind HT, Spoelstra NS, Babbs BL, Heinz RE, Elias A, Jedlicka P, Jacobsen BM, Richer JK. Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo. Mol Cancer Ther. 2015;14(3):769–78. Scholar
  11. 11.
    Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, Stearns V, Doane AS, Danso M, Moynahan ME, Momen LF, Gonzalez JM, Akhtar A, Giri DD, Patil S, Feigin KN, Hudis CA, Traina TA, Translational Breast Cancer Research C. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Clin Cancer Res. 2013;19(19):5505–12. Scholar
  12. 12.
    Lehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC, Chen X, Balko JM, Gomez H, Arteaga CL, Mills GB, Sanders ME, Pietenpol JA. PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res. 2014;16(4):406. Scholar
  13. 13.
    Robles AJ, Cai S, Cichewicz RH, Mooberry SL. Selective activity of deguelin identifies therapeutic targets for androgen receptor-positive breast cancer. Breast Cancer Res Treat. 2016;157(3):475–88. Scholar
  14. 14.
    Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O'Shaughnessy J, Gradishar W, Schmid P, Winer E, Kelly C, Nanda R, Gucalp A, Awada A, Garcia-Estevez L, Trudeau ME, Steinberg J, Uppal H, Tudor IC, Peterson A, Cortes J. Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol. 2018;36(9):884–90. Scholar
  15. 15.
    Fujii R, Hanamura T, Suzuki T, Gohno T, Shibahara Y, Niwa T, Yamaguchi Y, Ohnuki K, Kakugawa Y, Hirakawa H, Ishida T, Sasano H, Ohuchi N, Hayashi S. Increased androgen receptor activity and cell proliferation in aromatase inhibitor-resistant breast carcinoma. J Steroid Biochem Mol Biol. 2014;144:513–22. Scholar
  16. 16.
    Davis M, Tripathi S, Hughley R, He Q, Bae S, Karanam B, Martini R, Newman L, Colomb W, Grizzle W, Yates C. AR negative triple negative or “quadruple negative” breast cancers in African American women have an enriched basal and immune signature. PLoS ONE. 2018;13(6):e0196909. Scholar
  17. 17.
    Angajala A, Mothershed E, Davis MB, Tripathi S, He Q, Bedi D, Dean-Colomb W, Yates C. Quadruple negative breast cancers (qnbc) demonstrate subtype consistency among primary and recurrent or metastatic breast cancer. Translat Oncol. 2019;12(3):493–501. Scholar
  18. 18.
    Jovanovic B, Mayer IA, Mayer EL, Abramson VG, Bardia A, Sanders ME, Kuba MG, Estrada MV, Beeler JS, Shaver TM, Johnson KC, Sanchez V, Rosenbluth JM, Dillon PM, Forero-Torres A, Chang JC, Meszoely IM, Grau AM, Lehmann BD, Shyr Y, Sheng Q, Chen SC, Arteaga CL, Pietenpol JA. A randomized phase II neoadjuvant study of cisplatin, paclitaxel with or without everolimus in patients with stage II/III triple-negative breast cancer (TNBC): responses and long-term outcome correlated with increased frequency of dna damage response gene mutations, TNBC subtype, AR status, and Ki67. Clin Cancer Res. 2017;23(15):4035–45. Scholar
  19. 19.
    Yen MC, Kan JY, Hsieh CJ, Kuo PL, Hou MF, Hsu YL. Association of long-chain acyl-coenzyme A synthetase 5 expression in human breast cancer by estrogen receptor status and its clinical significance. Oncol Rep. 2017;37(6):3253–60. Scholar
  20. 20.
    Van Horn CG, Caviglia JM, Li LO, Wang S, Granger DA, Coleman RA. Characterization of recombinant long-chain rat acyl-CoA synthetase isoforms 3 and 6: identification of a novel variant of isoform 6. Biochemistry. 2005;44(5):1635–42. Scholar
  21. 21.
    Wu X, Li Y, Wang J, Wen X, Marcus MT, Daniels G, Zhang DY, Ye F, Wang LH, Du X, Adams S, Singh B, Zavadil J, Lee P, Monaco ME. Long chain fatty Acyl-CoA synthetase 4 is a biomarker for and mediator of hormone resistance in human breast cancer. PLoS ONE. 2013;8(10):e77060. Scholar
  22. 22.
    Monaco ME, Creighton CJ, Lee P, Zou X, Topham MK, Stafforini DM. Expression of long-chain fatty Acyl-CoA synthetase 4 in breast and prostate cancers is associated with sex steroid hormone receptor negativity. Translat Oncol. 2010;3(2):91–8.CrossRefGoogle Scholar
  23. 23.
    Orlando UD, Castillo AF, Medrano MAR, Solano AR, Maloberti PM, Podesta EJ. Acyl-CoA synthetase-4 is implicated in drug resistance in breast cancer cell lines involving the regulation of energy-dependent transporter expression. Biochem Pharmacol. 2019;159:52–63. Scholar
  24. 24.
    Radke S, Pirkmaier A, Germain D. Differential expression of the F-box proteins Skp2 and Skp2B in breast cancer. Oncogene. 2005;24(21):3448–58. Scholar
  25. 25.
    Zhang W, Cao L, Sun Z, Xu J, Tang L, Chen W, Luo J, Yang F, Wang Y, Guan X. Skp2 is over-expressed in breast cancer and promotes breast cancer cell proliferation. Cell Cycle. 2016;15(10):1344–51. Scholar
  26. 26.
    Fagan-Solis KD, Pentecost BT, Gozgit JM, Bentley BA, Marconi SM, Otis CN, Anderton DL, Schneider SS, Arcaro KF. SKP2 overexpression is associated with increased serine 10 phosphorylation of p27 (pSer10p27) in triple-negative breast cancer. J Cell Physiol. 2014;229(9):1160–9. Scholar
  27. 27.
    Naorem LD, Muthaiyan M. Integrated network analysis and machine learning approach for the identification of key genes of triple-negative breast cancer. J Cell Biochem. 2019;120(4):6154–67. Scholar
  28. 28.
    Stovgaard ES, Nielsen D, Hogdall E, Balslev E. Triple negative breast cancer—prognostic role of immune-related factors: a systematic review. Acta Oncol. 2018;57(1):74–82. Scholar
  29. 29.
    Wang K, Li HL, Xiong YF, Shi Y, Li ZY, Li J, Zhang X, Li HY. Development and validation of nomograms integrating immune-related genomic signatures with clinicopathologic features to improve prognosis and predictive value of triple-negative breast cancer: a gene expression-based retrospective study. Cancer Med. 2019;8(2):686–700. Scholar
  30. 30.
    Bottai G, Raschioni C, Losurdo A, Di Tommaso L, Tinterri C, Torrisi R, Reis-Filho JS, Roncalli M, Sotiriou C, Santoro A, Mantovani A, Loi S, Santarpia L. An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers. Breast Cancer Res. 2016;18(1):121. Scholar
  31. 31.
    Tomioka N, Azuma M, Ikarashi M, Yamamoto M, Sato M, Watanabe KI, Yamashiro K, Takahashi M. The therapeutic candidate for immune checkpoint inhibitors elucidated by the status of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression in triple negative breast cancer (TNBC). Breast Cancer. 2018;25(1):34–42. Scholar
  32. 32.
    Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM. Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci USA. 2002;99(24):15524–9. Scholar
  33. 33.
    Yonemori K, Kurahara H, Maemura K, Natsugoe S. MicroRNA in pancreatic cancer. J Hum Genet. 2017;62(1):33–40. Scholar
  34. 34.
    Koleckova M, Janikova M, Kolar Z. MicroRNAs in triple-negative breast cancer. Neoplasma. 2018;65(1):1–13. Scholar
  35. 35.
    Mathe A, Scott RJ, Avery-Kiejda KA. MiRNAs and Other Epigenetic Changes as Biomarkers in Triple Negative Breast Cancer. Int J Mol Sci. 2015;16(12):28347–76. Scholar
  36. 36.
    Ouyang M, Li Y, Ye S, Ma J, Lu L, Lv W, Chang G, Li X, Li Q, Wang S, Wang W. MicroRNA profiling implies new markers of chemoresistance of triple-negative breast cancer. PLoS ONE. 2014;9(5):e96228. Scholar
  37. 37.
    Eichelser C, Flesch-Janys D, Chang-Claude J, Pantel K, Schwarzenbach H. Deregulated serum concentrations of circulating cell-free microRNAs miR-17, miR-34a, miR-155, and miR-373 in human breast cancer development and progression. Clin Chem. 2013;59(10):1489–96. Scholar
  38. 38.
    Zeng Z, Chen X, Zhu D, Luo Z, Yang M. Low Expression of Circulating MicroRNA-34c is Associated with Poor Prognosis in Triple-Negative Breast Cancer. Yonsei Med J. 2017;58(4):697–702. Scholar
  39. 39.
    Niedzwiecki S, Piekarski J, Szymanska B, Pawlowska Z, Jeziorski A. Serum levels of circulating miRNA-21, miRNA-10b and miRNA-200c in triple-negative breast cancer patients. Ginekol Pol. 2018;89(8):415–20. Scholar
  40. 40.
    Freres P, Wenric S, Boukerroucha M, Fasquelle C, Thiry J, Bovy N, Struman I, Geurts P, Collignon J, Schroeder H, Kridelka F, Lifrange E, Jossa V, Bours V, Josse C, Jerusalem G. Circulating microRNA-based screening tool for breast cancer. Oncotarget. 2016;7(5):5416–28. Scholar
  41. 41.
    Changavi AA, Shashikala A, Ramji AS. Epidermal growth factor receptor expression in triple negative and nontriple negative breast carcinomas. J Lab Physicians. 2015;7(2):79–83. Scholar
  42. 42.
    Zhang L, Fang C, Xu X, Li A, Cai Q, Long X. Androgen receptor, EGFR, and BRCA1 as biomarkers in triple-negative breast cancer: a meta-analysis. Biomed Res Int. 2015. Scholar
  43. 43.
    Danzinger S, Tan YY. Differential claudin 3 and EGFR expression predicts BRCA1 mutation in triple-negative breast cancer. Cancer Invest. 2018;36(7):378–88. Scholar
  44. 44.
    Wang CQ, Li Y, Huang BF, Zhao YM, Yuan H, Guo D, Su CM, Hu GN, Wang Q, Long T, Wang Y, Tang CH, Li X. EGFR conjunct FSCN1 as a novel therapeutic strategy in triple-negative breast cancer. Sci Rep. 2017;7(1):15654. Scholar
  45. 45.
    Costa R, Shah AN, Santa-Maria CA, Cruz MR, Mahalingam D, Carneiro BA, Chae YK, Cristofanilli M, Gradishar WJ, Giles FJ. Targeting epidermal growth factor receptor in triple negative breast cancer: new discoveries and practical insights for drug development. Cancer Treat Rev. 2017;53:111–9. Scholar
  46. 46.
    Beltran AS, Graves LM, Blancafort P. Novel role of Engrailed 1 as a prosurvival transcription factor in basal-like breast cancer and engineering of interference peptides block its oncogenic function. Oncogene. 2014;33(39):4767–77. Scholar
  47. 47.
    Peluffo G, Subedee A, Harper NW. EN1 is a transcriptional dependency in triple-negative breast cancer associated with brain metastasis. Cancer Res. 2019;79(16):4173–83. Scholar
  48. 48.
    Sorolla A, Wang E, Clemons TD, Evans CW, Plani-Lam JH, Golden E, Dessauvagie B, Redfern AD, Swaminathan-Iyer K, Blancafort P. Triple-hit therapeutic approach for triple negative breast cancers using docetaxel nanoparticles, EN1-iPeps and RGD peptides. Nanomed Nanotechnol Biol Med. 2019;20:102003. Scholar
  49. 49.
    Kim YJ, Sung M, Oh E, Vrancken MV, Song JY, Jung K, Choi YL. Engrailed 1 overexpression as a potential prognostic marker in quintuple-negative breast cancer. Cancer Biol Ther. 2018;19(4):335–45. Scholar

Copyright information

© The Japanese Breast Cancer Society 2020

Authors and Affiliations

  1. 1.Department of Thyroid, Breast and Vascular SurgeryXijing Hospital, The Fourth Military Medical UniversityXi’anChina

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