Immunohistochemical subtyping and evaluation of the prognosis of basal-like triple-negative breast cancer based on IDO1 protein expression

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


Background. Known subtypes of triple-negative breast cancer, despite the common basal-like profile, have certain features that differ in terms of the course and prognosis of the disease. Therefore, the study of molecular markers that make it possible to identify subtypes of basal-like carcinomas and evaluate a probable prognosis based on their expression indicators is relevant today.

Aim. Conduct immunohistochemical subtyping of basal-like triple-negative breast cancer based on the assessment of IDO1 protein expression, compare the obtained data with clinical and morphological characteristics, as well as indicators of tumor sensitivity to neoadjuvant therapy.

Material and methods. The study was retrospective and included 42 patients diagnosed with triple negative breast cancer (mean age 50.5±12.7 years), disease stage T1–4dN0–3M0. The patients were treated in the Departments of Chemotherapy and General Oncology of the Research Institute of Oncology of the Tomsk National Research Medical Center from 2016 to 2021. A morphological study of tumor tissue samples, breast core biopsies, and surgical material was performed. Immunohistochemical study was carried out on sections of core biopsies. The expression of markers was evaluated, the obtained data were compared with clinical and morphological characteristics, as well as with indicators of tumor sensitivity to neoadjuvant therapy. Statistical analysis was carried out using the Statistica 10.0 program, data comparison was performed using the methods of descriptive statistics and nonparametric method of Pearson's χ2 test.

Results. The immunoactivated subtype was determined with the status of CK5/6+/IDO1+ carcinomas, such tumors were dominant and accounted for 81.25% (n=26/32). In these cases (CK5/6+/IDO1+), the presence of metastatic lesions in the axillary lymph nodes was statistically significantly less common, and the frequency of complete pathomorphological regression was higher than in carcinomas, the molecular profile of which corresponds to the immunosuppressive subtype (CK5/6+/IDO1–).

Conclusion. Expression of the IDO1 protein may serve as a molecular and biological marker allowing immunohistochemical identification of subtypes of basal-like triple-negative breast cancer.

Full Text

Restricted Access

About the authors

Nadezhda V. Krakhmal

Research Institute of Oncology of the Tomsk National Research Medical Center of the Russian Academy of Sciences; Siberian State Medical University

ORCID iD: 0000-0002-1909-1681
SPIN-code: 1543-6546

M.D., Cand. Sci. (Med.), Senior Researcher, Department of General and Molecular Pathology; Assoc. Prof., Depart. of Pathology

Russian Federation, Tomsk, Russia; Tomsk, Russia

Valeriia O. Tarakanova

Research Institute of Oncology of the Tomsk National Research Medical Center of the Russian Academy of Sciences; Siberian State Medical University

ORCID iD: 0000-0001-9472-017X

M.D., Postgraduate, Depart. of Cancer Research Institute; Assistant, Depart. of Oncology

Russian Federation, Tomsk, Russia; Tomsk, Russia

Sergey V. Vtorushin

Research Institute of Oncology of the Tomsk National Research Medical Center of the Russian Academy of Sciences; Siberian State Medical University

Author for correspondence.
ORCID iD: 0000-0002-1195-4008

M.D., D. Sci. (Med.), Prof., Head of Depart., Depart. of General and Molecular Pathology; Prof., Depart. of Pathology

Russian Federation, Tomsk, Russia; Tomsk, Russia


  1. Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist. 2011;16(1):61–70. doi: 10.1634/theoncologist.2011-S1-61.
  2. Bertucci F, Finetti P, Birnbaum D. Basal breast cancer: A complex and deadly molecular subtype. Curr Mol Med. 2012;12(1):96–110. doi: 10.2174/156652412798376134.
  3. The WHO Classification of Tumours Editorial Board. Breast tumours. WHO Classification of Tumours. 5th ed. Vol. 2. Lyon: IARC-Press; 2019. p. 10.
  4. 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. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367–5374. doi: 10.1158/1078-0432.CCR-04-0220.
  5. Le Du F, Eckhardt BL, Lim B, Litton JK, Moulder S, Meric-Bernstam F, Gonzalez-Angulo AM, Ueno NT. Is the future of personalized therapy in triple-negative breast cancer based on molecular subtype? Oncotarget. 2015;6(15):12890–12908. doi: 10.18632/oncotarget.3849.
  6. Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SA, Savage MI, Osborne CK, Hilsenbeck SG, Chang JC, Mills GB, Lau CC, Brown PH. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res. 2015;21(7):1688–1698. doi: 10.1158/1078-0432.CCR-14-0432.
  7. Аmir Hassan Zadeh, Qamar Alsabi, Jaime E, Ramirez-Vick, Nasim Nosoudi. Characterizing basal-like triple negative breast cancer using gene expression analysis: A data mining approach. Expert Systems with Applications. 2020;148:113253. doi: 10.1016/j.eswa.2020.113253.
  8. Yin L, Duan JJ, Bian XW, Yu SC. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 2020;22(1):61. doi: 10.1186/s13058-020-01296-5.
  9. Kim S, Moon BI, Lim W, Park S, Cho MS, Sung SH. Feasibility of classification of triple negative breast cancer by immunohistochemical surrogate markers. Clin Breast Cancer. 2018;18(5):e1123–e1132. doi: 10.1016/j.clbc.2018.03.012.
  10. Santonja A, Sánchez-Muñoz A, Lluch A, Chica-Parrado MR, Albanell J, Chacón JI, Antolín S, Jerez JM, de la Haba J, de Luque V, Fernández-De Sousa CE, Vicioso L, Plata Y, Ramírez-Tortosa CL, Álvarez M, Llácer C, Zarcos-Pedrinaci I, Carrasco E, Caballero R, Martín M, Alba E. Triple negative breast cancer subtypes and pathologic complete response rate to neoadjuvant chemotherapy. Oncotarget. 2018;9(41):26406–26416. doi: 10.18632/oncotarget.25413.
  11. Lehmann BD, Jovanović B, Chen X, Estrada MV, Johnson KN, Shyr Y, Moses HL, Sanders ME, Pietenpol JA. Refinement of triple-negative breast cancer molecular subtypes: Implications for neoadjuvant chemotherapy selection. PLoS One. 2016;11(6):e0157368. doi: 10.1371/journal.pone.0157368.
  12. 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):176–198. doi: 10.1158/2159-8290.CD-18-1177.
  13. Mehanna J, Haddad Fady HD, Eid R, Lambertini M, Kourie HR. Triple-negative breast cancer: Current perspective on the evolving therapeutic landscape. Int J Women Health. 2019;11:431–437. doi: 10.2147/IJWH.S178349.
  14. Kim S, Park S, Cho MS, Lim W, Moon BI, Sung SH. Strong correlation of indoleamine 2,3-dioxygenase 1 expression with basal-like phenotype and increased lymphocytic infiltration in triple-negative breast cancer. J Cancer. 2017;8(1):124–130. doi: 10.7150/jca.17437.
  15. Liu M, Wang X, Wang L, Ma X, Gong Z, Zhang S, Li Y. Targeting the IDO1 pathway in cancer: from bench to bedside. J Hematol Oncol. 2018;11(1):100. doi: 10.1186/s13045-018-0644-y.
  16. Li F, Zhang R, Li S, Liu J. IDO1: An important immunotherapy target in cancer treatment. Int Immunopharmacol. 2017;47:70–77. doi: 10.1016/j.intimp.2017.03.024.
  17. Zhai L, Bell A, Ladomersky E, Lauing KL, Bollu L, Sosman JA, Zhang B, Wu JD, Miller SD, Meeks JJ, Lukas RV, Wyatt E, Doglio L, Schiltz GE, McCus-ker RH, Wainwright DA. Immunosuppressive IDO in cancer: Mechanisms of action, animal models, and targeting strategies. Front Immunol. 2020;11:1185. doi: 10.3389/fimmu.2020.01185.
  18. Tang K, Wu YH, Song Y, Yu B. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy. J Hematol Oncol. 2021;14(1):68. doi: 10.1186/s13045-021-01080-8.
  19. Amobi-McCloud A, Muthuswamy R, Battaglia S, Yu H, Liu T, Wang J, Putluri V, Singh PK, Qian F, Huang RY, Putluri N, Tsuji T, Lugade AA, Liu S, Odunsi K. IDO1 expression in ovarian cancer induces PD-1 in T cells via Aryl hydrocarbon receptor activation. Front Immunol. 2021;12:678999. doi: 10.3389/fimmu.2021.678999.
  20. Xiang Z, Li J, Song S, Wang J, Cai W, Hu W, Ji J, Zhu Z, Zang L, Yan R, Yu Y. A positive feedback between IDO1 metabolite and COL12A1 via MAPK pathway to promote gastric cancer metastasis. J Exp Clin Cancer Res. 2019;38(1):314. doi: 10.1186/s13046-019-1318-5.
  21. Newman AC, Falcone M, Huerta Uribe A, Zhang T, Athineos D, Pietzke M, Vazquez A, Blyth K, Maddocks ODK. Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells. Mol Cell. 2021;81(11):2290–2302.e7. doi: 10.1016/j.molcel.2021.03.019.
  22. Kovaleva OV, Rashidova MA, Gratchev AN, Maslennikov VV, Boulitcheva IV, Gershtein ES, Korotkova EA, Sokolov NY, Delektorskaya VV, Mamedli ZZ, Kushlinskii NE. Immunosuppression factors PD-1, PD-L1, and IDO1 and colorectal cancer. Dokl Biochem Biophys. 2021;497(1):66–70. doi: 10.1134/S1607672921020095.
  23. Yang SL, Tan HX, Niu TT, Liu YK, Gu CJ, Li DJ, Li MQ, Wang HY. The IFN-γ-IDO1-kynureine pathway-induced autophagy in cervical cancer cell promotes phagocytosis of macrophage. Int J Biol Sci. 2021;17(1):339–352. doi: 10.7150/ijbs.51241.
  24. Kovaleva OV, Rashidova MA, Mochalnikova VV, Samoilova DV, Polesnaya PA, Gratchev AN. Prognostic significance of CD204 and IDO1 expression in esophageal tumors. Advances in Molecular Oncology. 2021;8(2):40–46. (In Russ.) doi: 10.17650/2313-805X-2021-8-2-40-46.
  25. Kovaleva OV, Rashidova MA, Samoilova DV, Podlesnaya PA, Tabiev RM, Kuntsevich NV, Efremov GD, Alekseev BYa, Gratchev AN. Immunosuppressive peculiarities of stromal cells of various kidney tumor types. Cancer Urology. 2020;16(2):29–35. (In Russ.) doi: 10.17650/1726-9776-2020-16-2-29-35.
  26. Dill EA, Dillon PM, Bullock TN, Mills AM. IDO expression in breast cancer: An assessment of 281 primary and metastatic cases with comparison to PD-L1. Mod Pathol. 2018;31(10):1513–1522. doi: 10.1038/s41379-018-0061-3.
  27. Fang J, Chen F, Liu D, Gu F, Chen Z, Wang Y. Prognostic value of immune checkpoint molecules in breast cancer. Biosci Rep. 2020;40(7):BSR20201054. doi: 10.1042/BSR20201054.
  28. Wei JL, Wu SY, Yang YS, Xiao Y, Jin X, Xu XE, Hu X, Li DQ, Jiang YZ, Shao ZM. GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer. J Immunother Cancer. 2021;9(7):e002383. doi: 10.1136/jitc-2021-002383.
  29. Dowsett M, Nielsen TO, A'Hern R, Bartlett J, Coombes RC, Cuzick J, Ellis M, Henry NL, Hugh JC, Lively T, McShane L, Paik S, Penault-Llorca F, Prudkin L, Regan M, Salter J, Sotiriou C, Smith IE, Viale G, Zujewski JA, Hayes DF. International Ki-67 in Breast Cancer Working Group. Assessment of Ki67 in breast cancer: Recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103(22):1656–1664. doi: 10.1093/jnci/djr393.
  30. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25(28):4414–4422. doi: 10.1200/JCO.2007.10.6823.
  31. Jacquemier J, Bertucci F, Finetti P, Esterni B, Charafe-Jauffret E, Thibult ML, Houvenaeghel G, Van den Eynde B, Birnbaum D, Olive D, Xerri L. High expression of indoleamine 2,3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal-like breast carcinoma. Int J Cancer. 2012;130(1):96–104. doi: 10.1002/ijc.25979.

Supplementary files

Supplementary Files
1. Рис. 1. Экспрессия белка IDO1 в опухолевой ткани при тройном негативном раке молочной железы (ТНРМЖ). А. Отсутствие экспрессии белка IDO1 в опухоли при базальноподобном ТНРМЖ (негативная экспрессия маркёра). Иммуногистохимическое исследование, увеличение ×200. Б. Наличие цитоплазматической экспрессии белка IDO1 в опухоли при базальноподобном ТНРМЖ (позитивная экспрессия маркёра). Иммуногистохимическое исследование, увеличение ×400

Download (103KB)
2. Рис. 2. Лечебный патоморфоз CK5/6+/IDO1+ (тип 1) и CK5/6+/IDO1− (тип 2) опухолей в группе исследования базальноподобных карцином — тройного негативного рака молочной железы (ТНРМЖ) (система RCB). А. Полный патоморфологический регресс опухоли (pCR) в случае CK5/6+/IDO1+ ТНРМЖ (тип 1). Окраска гематоксилином и эозином. Увеличение ×100. Б. Выраженная остаточная опухоль (RCB III) в случае CK5/6+/IDO1− ТНРМЖ (тип 2). Окраска гематоксилином и эозином. Увеличение ×100

Download (147KB)

© 2023 Eco-Vector

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies