Pathology & Oncology Research

, Volume 24, Issue 2, pp 259–267 | Cite as

Immunohistochemical Analysis of the Expression of Breast Markers in Basal-like Breast Carcinomas Defined as Triple Negative Cancers Expressing Keratin 5

Original Article


Estrogen and progesterone receptors are possible markers for suggesting a mammary origin of metastatic carcinoma, but are useless in cases of triple negative breast cancers (TNBC). Five other potential markers of breast origin were investigated on tissue microarrays in a series of TNBCs showing keratin 5 expression, consistent with a basal-like phenotype. GATA-3 staining was observed in 82 of 115 triple negative cases (71.3%) including 23 cases with >5% staining. Mammaglobin staining was detected in 30 cases (26.0%) including 12 with >5% staining. GCDFP-15 was seen in 23 cases (20.0%) including 9 with >5% staining. NY-BR-1 positivity was present in 7 cases (6.0%) including 3 patients with >5% staining. BCA-225 staining was observed in 74 cases (64.3%); however this latter marker lacks also specificity owing to the reported widespread staining in other malignancies. GATA-3, mammaglobin and GCDFP-15 coexpression was seen in one case (0.9%), whereas GATA-3 and mammaglobin or mammaglobin and GCDFP-15 coexpression was present in 2 and 2 cases (1.7%), respectively. Using at least 5% staining as cut-off, the expression of any of the last 4 markers was 34.7%. The expression of GATA-3, mammaglobin, GCDFP-15 and NY-BR-1 is lower in TNBC-s than in breast carcinomas in general, and this may be even lower in basal-like carcinomas. Although these markers are not fully specific, by using them, a subset of basal-like TNBC-s can be identified as of mammary origin. However, a substantial proportion will not show any staining with any of these markers.


Basal-like Triple negative breast cancer GATA-3 Mammaglobin GCDFP-15 NY-BR-1 



This study was funded by the National Research, Development and Innovation Office grant GINOP-2.3.2-15-2016-00020.

Compliance with Ethical Standards

Conflict of Interest

No editorial or financial conflicts of interest exist for this submission.


  1. 1.
    DeSantis C, Ma J, Bryan L, Jemal A (2013) Breast cancer statistics, 2013. CA Cancer J Clin 64:52–62. doi: 10.3322/caac.21203 CrossRefPubMedGoogle Scholar
  2. 2.
    Malvezzi M, Carioli G, Bertuccio P, Rosso T, Boffetta P, Levi F, La Vecchia C, Negri E (2016) European cancer mortality predictions for the year 2016 with focus on leukaemias. Ann Oncol 27:725–731. doi: 10.1093/annonc/mdw022 CrossRefPubMedGoogle Scholar
  3. 3.
    Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406:747–752CrossRefPubMedGoogle Scholar
  4. 4.
    Nielsen TO, Perou CM (2015) CCR 20th anniversary commentary: the development of breast cancer molecular subtyping. Clin Cancer Res 21:1779–1781. doi: 10.1158/1078-0432.CCR-14-2552 CrossRefPubMedGoogle Scholar
  5. 5.
    Hernandez BY, Green MD, Cassel KD, Pobutsky AM, Vu V, Wilkens LR (2010) Preview of Hawaii cancer facts and figures. Hawaii Med J 69:223–224PubMedPubMedCentralGoogle Scholar
  6. 6.
    Huo L, Gong Y, Guo M, Gilcrease MZ, Wu Y, Zhang H, Zhang J, Resetkova E, Hunt KK, Deavers MT (2015) GATA-binding protein 3 enhances the utility of gross cystic disease fluid protein-15 and mammaglobin a in triple-negative breast cancer by immunohistochemistry. Histopathology 67:245–254. doi: 10.1111/his.12645 CrossRefPubMedGoogle Scholar
  7. 7.
    Deftereos G, Sanguino Ramirez AM, Silverman JF, Krishnamurti U (2015) GATA3 immunohistochemistry expression in histologic subtypes of primary breast carcinoma and metastatic breast carcinoma cytology. Am J Surg Pathol 39:1282–1289. doi: 10.1097/PAS.0000000000000505 CrossRefPubMedGoogle Scholar
  8. 8.
    Chou J, Provot S, Werb Z (2010) GATA3 in development and cancer differentiation: cells GATA have it! J Cell Physiol 222:42–49. doi: 10.1002/jcp.21943 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Esheba GE, Longacre TA, Atkins KA, Higgins JP (2009) Expression of the urothelial differentiation markers GATA3 and placental S100 (S100P) in female genital tract transitional cell proliferations. Am J Surg Pathol 33:347–353CrossRefPubMedGoogle Scholar
  10. 10.
    Liu H, Shi J, Wilkerson ML, Lin F (2012) Immunohistochemical evaluation of GATA3 expression in tumors and normal tissues: a useful immunomarker for breast and urothelial carcinomas. Am J Clin Pathol 138:57–64. doi: 10.1309/AJCP5UAFMSA9ZQBZ CrossRefPubMedGoogle Scholar
  11. 11.
    Ordonez NG (2013) Value of GATA3 immunostaining in tumor diagnosis: a review. Adv Anat Pathol 20:352–360. doi: 10.1097/PAP.0b013e3182a28a68 CrossRefPubMedGoogle Scholar
  12. 12.
    Miettinen M, McCue PA, Sarlomo-Rikala M, Rys J, Czapiewski P, Wazny K, Langfort R, Waloszczyk P, Biernat W, Lasota J, Wang Z (2014) GATA3: a multispecific but potentially useful marker in surgical pathology: a systematic analysis of 2500 epithelial and nonepithelial tumors. Am J Surg Pathol 38:13–22. doi: 10.1097/PAS.0b013e3182a0218f CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Voduc D, Cheang M, Nielsen T (2008) GATA-3 expression in breast cancer has a strong association with estrogen receptor but lacks independent prognostic value. Cancer Epidemiol Biomark Prev 17:365–373. doi: 10.1158/1055-9965.EPI-06-1090 CrossRefGoogle Scholar
  14. 14.
    Hoch RV, Thompson DA, Baker RJ, Weigel RJ (1999) GATA-3 is expressed in association with estrogen receptor in breast cancer. Int J Cancer 84:122–128CrossRefPubMedGoogle Scholar
  15. 15.
    Tominaga N, Naoi Y, Shimazu K, Nakayama T, Maruyama N, Shimomura A, Kim SJ, Tamaki Y, Noguchi S (2012) Clinicopathological analysis of GATA3-positive breast cancers with special reference to response to neoadjuvant chemotherapy. Ann Oncol 23:3051–3057. doi: 10.1093/annonc/mds120 CrossRefPubMedGoogle Scholar
  16. 16.
    Albergaria A, Paredes J, Sousa B, Milanezi F, Carneiro V, Bastos J, Costa S, Vieira D, Lopes N, Lam EW, Lunet N, Schmitt F (2009) Expression of FOXA1 and GATA-3 in breast cancer: the prognostic significance in hormone receptor-negative tumours. Breast Cancer Res 11:R40. doi: 10.1186/bcr2327 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Parikh P, Palazzo JP, Rose LJ, Daskalakis C, Weigel RJ (2005) GATA-3 expression as a predictor of hormone response in breast cancer. J Am Coll Surg 200:705–710CrossRefPubMedGoogle Scholar
  18. 18.
    Mehra R, Varambally S, Ding L, Shen R, Sabel MS, Ghosh D, Chinnaiyan AM, Kleer CG (2005) Identification of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis. Cancer Res 65:11259–11264CrossRefPubMedGoogle Scholar
  19. 19.
    Cimino-Mathews A, Subhawong AP, Illei PB, Sharma R, Halushka MK, Vang R, Fetting JH, Park BH, Argani P (2013) GATA3 expression in breast carcinoma: utility in triple-negative, sarcomatoid, and metastatic carcinomas. Hum Pathol 44:1341–1349. doi: 10.1016/j.humpath.2012.11.003 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ciocca V, Daskalakis C, Ciocca RM, Ruiz-Orrico A, Palazzo JP (2009) The significance of GATA3 expression in breast cancer: a 10-year follow-up study. Hum Pathol 40:489–495. doi: 10.1016/j.humpath.2008.09.010 CrossRefPubMedGoogle Scholar
  21. 21.
    Jacquemier J, Charafe-Jauffret E, Monville F, Esterni B, Extra JM, Houvenaeghel G, Xerri L, Bertucci F, Birnbaum D (2009) Association of GATA3, P53, Ki67 status and vascular peritumoral invasion are strongly prognostic in luminal breast cancer. Breast Cancer Res 11:R23. doi: 10.1186/bcr2249 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Demir H, Turna H, Can G, Ilvan S (2010) Clinicopathologic and prognostic evaluation of invasive breast carcinoma molecular subtypes and GATA3 expression. J Buon 15:774–782PubMedGoogle Scholar
  23. 23.
    Watson MA, Fleming TP (1996) Mammaglobin, a mammary-specific member of the uteroglobin gene family, is overexpressed in human breast cancer. Cancer Res 56:860–865PubMedGoogle Scholar
  24. 24.
    Watson MA, Darrow C, Zimonjic DB, Popescu NC, Fleming TP (1998) Structure and transcriptional regulation of the human mammaglobin gene, a breast cancer associated member of the uteroglobin gene family localized to chromosome 11q13. Oncogene 16:817–824CrossRefPubMedGoogle Scholar
  25. 25.
    Han JH, Kang Y, Shin HC, Kim HS, Kang YM, Kim YB, Oh SY (2003) Mammaglobin expression in lymph nodes is an important marker of metastatic breast carcinoma. Arch Pathol Lab Med 127:1330–1334PubMedGoogle Scholar
  26. 26.
    Bhargava R, Beriwal S, Dabbs DJ (2007) Mammaglobin vs GCDFP-15: an immunohistologic validation survey for sensitivity and specificity. Am J Clin Pathol 127:103–113CrossRefPubMedGoogle Scholar
  27. 27.
    Zafrakas M, Petschke B, Donner A, Fritzsche F, Kristiansen G, Knüchel R, Dahl E (2006) Expression analysis of mammaglobin a (SCGB2A2) and lipophilin B (SCGB1D2) in more than 300 human tumors and matching normal tissues reveals their co-expression in gynecologic malignancies. BMC Cancer 6:88CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Sasaki E, Tsunoda N, Hatanaka Y, Mori N, Iwata H, Yatabe Y (2007) Breast-specific expression of MGB1/mammaglobin: an examination of 480 tumors from various organs and clinicopathological analysis of MGB1-positive breast cancers. Mod Pathol 20:208–214CrossRefPubMedGoogle Scholar
  29. 29.
    Wang Z, Spaulding B, Sienko A, Liang Y, Li H, Nielsen G, Yub Gong G, Ro JY, Jim Zhai Q (2009) Mammaglobin, a valuable diagnostic marker for metastatic breast carcinoma. Int J Clin Exp Pathol 2:384–389PubMedGoogle Scholar
  30. 30.
    Onuma K, Dabbs DJ, Bhargava R (2008) Mammaglobin expression in the female genital tract: immunohistochemical analysis in benign and neoplastic endocervix and endometrium. Int J Gynecol Pathol 27:418–425. doi: 10.1097/PGP.0b013e31815d05ec CrossRefPubMedGoogle Scholar
  31. 31.
    Al-Joudi FS, Kaid FA, Ishak I, Mohamed N, Osman K, Alias IZ (2011) Expression of human mammaglobin and clinicopathologic correlations in breast cancer: the findings in Malaysia. Indian J Pathol Microbiol 54:284–289. doi: 10.4103/0377-4929.81596 CrossRefPubMedGoogle Scholar
  32. 32.
    Lewis GH, Subhawong AP, Nassar H, Vang R, Illei PB, Park BH, Argani P (2011) Relationship between molecular subtype of invasive breast carcinoma and expression of gross cystic disease fluid protein 15 and mammaglobin. Am J Clin Pathol 135:587–591. doi: 10.1309/AJCPMFR6OA8ICHNH CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Fritzsche FR, Thomas A, Winzer KJ, Beyer B, Dankof A, Bellach J, Dahl E, Dietel M, Kristiansen G (2007) Co-expression and prognostic value of gross cystic disease fluid protein 15 and mammaglobin in primary breast cancer. Histol Histopathol 22:1221–1230PubMedGoogle Scholar
  34. 34.
    Haagensen DE Jr, Mazoujian G, Holder WD Jr, Kister SJ, Wells SA Jr (1977) Evaluation of a breast cyst fluid protein detectable in the plasma of breast carcinoma patients. Ann Surg 185:279–285CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wick MR, Lillemoe TJ, Copland GT, Swanson PE, Manivel JC, Kiang DT (1989) Gross cystic disease fluid protein-15 as a marker for breast cancer: immunohistochemical analysis of 690 human neoplasms and comparison with alpha-lactalbumin. Hum Pathol 20:281–287CrossRefPubMedGoogle Scholar
  36. 36.
    Park SY, Kim BH, Kim JH, Lee S, Kang GH (2007) Panels of immunohistochemical markers help determine primary sites of metastatic adenocarcinoma. Arch Pathol Lab Med 131:1561–1567PubMedGoogle Scholar
  37. 37.
    Jäger D, Stockert E, Güre AO, Scanlan MJ, Karbach J, Jäger E, Knuth A, Old LJ, Chen YT (2001) Identification of a tissue-specific putative transcription factor in breast tissue by serological screening of a breast cancer library. Cancer Res 61:2055–2061PubMedGoogle Scholar
  38. 38.
    Jäger D, Filonenko V, Gout I, Frosina D, Eastlake-Wade S, Castelli S, Varga Z, Moch H, Chen YT, Busam KJ, Seil I, Old LJ, Nissan A, Frei C, Gure AO, Knuth A, Jungbluth AA (2007) NY-BR-1 is a differentiation antigen of the mammary gland. Appl Immunohistochem Mol Morphol 15:77–83CrossRefPubMedGoogle Scholar
  39. 39.
    Giger OT, Lacoste E, Honegger C, Padberg B, Moch H, Varga Z (2007) Expression of the breast differentiation antigen NY-BR-1 in a phyllodes tumor of the vulva. Virchows Arch 450:471–474CrossRefPubMedGoogle Scholar
  40. 40.
    Varga Z, Theurillat JP, Filonenko V, Sasse B, Odermatt B, Jungbluth AA, Chen YT, Old LJ, Knuth A, Jäger D, Moch H (2006) Preferential nuclear and cytoplasmic NY-BR-1 protein expression in primary breast cancer and lymph node metastases. Clin Cancer Res 12:2745–2751CrossRefPubMedGoogle Scholar
  41. 41.
    Theurillat JP, Zürrer-Härdi U, Varga Z, Storz M, Probst-Hensch NM, Seifert B, Fehr MK, Fink D, Ferrone S, Pestalozzi B, Jungbluth AA, Chen YT, Jäger D, Knuth A, Moch H (2007) NY-BR-1 protein expression in breast carcinoma: a mammary gland differentiation antigen as target for cancer immunotherapy. Cancer Immunol Immunother 56:1723–1731CrossRefPubMedGoogle Scholar
  42. 42.
    Seil I, Frei C, Sültmann H, Knauer SK, Engels K, Jäger E, Zatloukal K, Pfreundschuh M, Knuth A, Tseng-Chen Y, Jungbluth AA, Stauber RH, Jäger D (2007) The differentiation antigen NY-BR-1 is a potential target for antibody-based therapies in breast cancer. Int J Cancer 120:2635–2642CrossRefPubMedGoogle Scholar
  43. 43.
    Woodard AH, Yu J, Dabbs DJ, Beriwal S, Florea AV, Elishaev E, Davison JM, Krasinskas AM, Bhargava R (2011) NY-BR-1 and PAX8 immunoreactivity in breast, gynecologic tract, and other CK7+ carcinomas: potential use for determining site of origin. Am J Clin Pathol 136:428–435. doi: 10.1309/AJCPUFNMEZ3MK1BK CrossRefPubMedGoogle Scholar
  44. 44.
    Balafoutas D, zur Hausen A, Mayer S, Hirschfeld M, Jaeger M, Denschlag D, Gitsch G, Jungbluth A, Stickeler E (2013) Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prognostic and therapeutic implications. BMC Cancer 13:271. doi: 10.1186/1471-2407-13-271 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Liu H (2014) Application of immunohistochemistry in breast pathology: a review and update. Arch Pathol Lab Med 138:1629–1642. doi: 10.5858/arpa.2014-0094-RA CrossRefPubMedGoogle Scholar
  46. 46.
    Mesa-Tejada R, Palakodety RB, Leon JA, Khatcherian AO, Greaton CJ (1988) Immunocytochemical distribution of a breast carcinoma associated glycoprotein identified by monoclonal antibodies. Am J Pathol 130:305–314PubMedPubMedCentralGoogle Scholar
  47. 47.
    Loy TS, Chapman RK, Diaz-Arias AA, Bulatao IS, Bickel JT (1991) Distribution of BCA-225 in adenocarcinomas. An immunohistochemical study of 446 cases. Am J Clin Pathol 96:326–329CrossRefPubMedGoogle Scholar
  48. 48.
    Abramson VG, Lehmann BD, Ballinger TJ, Pietenpol JA (2015) Subtyping of triple-negative breast cancer: implications for therapy. Cancer 121:8–16. doi: 10.1002/cncr.28914 CrossRefPubMedGoogle Scholar
  49. 49.
    Vranic S, Schmitt F, Sapino A, Costa JL, Reddy S, Castro M, Gatalica Z (2013) Apocrine carcinoma of the breast: a comprehensive review. Histol Histopathol 28:1393–1409. doi: 10.14670/HH-28.1393 PubMedGoogle Scholar
  50. 50.
    Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374CrossRefPubMedGoogle Scholar
  51. 51.
    Sasahara M, Matsui A, Ichimura Y, Hirakata Y, Murata Y, Marui E (2014) Overexpression of androgen receptor and forkhead-box A1 protein in apocrine breast carcinoma. Anticancer Res 34:1261–1267PubMedGoogle Scholar
  52. 52.
    Kővári B, Rusz O, Schally AV, Kahán Z, Cserni G (2014) Differential immunostaining of various types of breast carcinomas for growth hormone-releasing hormone (GHRH) receptor - apocrine epithelium and carcinomas emerging as uniformly positive. APMIS 122:824–831. doi: 10.1111/apm.12224 CrossRefPubMedGoogle Scholar
  53. 53.
    Ordonez NG, Sahin AA (2014) Diagnostic utility of immunohistochemistry in distinguishing between epithelioid pleural mesotheliomas and breast carcinomas: a comparative study. Hum Pathol 45:1529–1540. doi: 10.1016/j.humpath.2014.03.006 CrossRefPubMedGoogle Scholar
  54. 54.
    Krings G, Nystrom M, Mehdi I, Vohra P, Chen YY (2014) Diagnostic utility and sensitivities of GATA3 antibodies in triple-negative breast cancer. Hum Pathol 45:2225–2232. doi: 10.1016/j.humpath.2014.06.022 CrossRefPubMedGoogle Scholar
  55. 55.
    Braxton DR, Cohen C, Siddiqui MT (2015) Utility of GATA3 immunohistochemistry for diagnosis of metastatic breast carcinoma in cytology specimens. Diagn Cytopathol 43:271–277. doi: 10.1002/dc.23206 CrossRefPubMedGoogle Scholar
  56. 56.
    Lew M, Pang JC, Jing X, Fields KL, Roh MH (2015) Young investigator challenge: the utility of GATA3 immunohistochemistry in the evaluation of metastatic breast carcinomas in malignant effusions. Cancer Cytopathol 123:576–581. doi: 10.1002/cncy.21574 CrossRefPubMedGoogle Scholar
  57. 57.
    Rakhshani N, Daryakar A (2014) Are mammaglobin and GCDFP-15 sensitive markers for diagnosis of metastatic basal-like triple negative breast carcinomas? Turk Patoloji Derg 30:18–22. doi: 10.5146/tjpath.2013.01202 PubMedGoogle Scholar
  58. 58.
    Darb-Esfahani S, von Minckwitz G, Denkert C, Ataseven B, Högel B, Mehta K, Kaltenecker G, Rüdiger T, Pfitzner B, Kittel K, Fiedler B, Baumann K, Moll R, Dietel M, Eidtmann H, Thomssen C, Loibl S (2014) Gross cystic disease fluid protein 15 (GCDFP-15) expression in breast cancer subtypes. BMC Cancer 14:546. doi: 10.1186/1471-2407-14-546 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Pala EE, Bayol Ü, Cumurcu S, Keskın E (2012) Immunohistochemical characteristics of triple negative/basal-like breast cancer. Turk Patoloji Derg 28:238–244. doi: 10.5146/tjpath.2012.01130 PubMedGoogle Scholar
  60. 60.
    Clark BZ, Beriwal S, Dabbs DJ, Bhargava R (2014) Semiquantitative GATA-3 immunoreactivity in breast, bladder, gynecologic tract, and other cytokeratin 7-positive carcinomas. Am J Clin Pathol 142:64–71. doi: 10.1309/AJCP8H2VBDSCIOBF CrossRefPubMedGoogle Scholar
  61. 61.
    Gloyeske NC1, Woodard AH, Elishaev E, Yu J, Clark BZ, Dabbs DJ, Bhargava R (2015) Immunohistochemical profile of breast cancer with respect to estrogen receptor and HER2 status. Appl Immunohistochem Mol Morphol 23:202–208. doi: 10.1097/PAI.0000000000000076 CrossRefPubMedGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2017

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Szeged, Faculty of MedicineSzegedHungary
  2. 2.Department of PathologyBács-Kiskun County Teaching HospitalKecskemétHungary

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