ALDH1A1 POSITIVE TUMOR CELLS AND THEIR EFFECT ON THE SIGNALING PATHWAYS OF NF-kB, PI3K PTEN, NOTCH, WNT, Hedgehog IN CASES OF TRIPLE NEGATIVE AND HORMONE RECEPTOR NEGATIVE HER2 POSITIVE IMMUNOHISTOCHEMICAL SUBTYPES OF BREAST CANCER

DOI: 10.22138/2500-0918-2019-16-1-41-49

A.A. Brilliant, Y.M. Brilliant, S.V. Sazonov, S.A. Denisenko, S.M. Demidov, S.L. Leontiev

Institute of Medical Cell Technologies, Yekaterinburg, Russian Federation;
Ural State Medical University, Yekaterinburg, Russian Federation

Abstract. The aim of the research was to study the pool of tumor stem cells in different immunohistochemical subtypes of infiltrative breast cancer. Analyze possible changes in the expression of the NF-kB, PI3K PTEN, NOTCH, WNT, Hedgehog signaling pathways in Triple Negative and Hormone receptor negative HER2 positive subtypes. Materials and methods. We used material from 110 cases of breast cancer. To determine the stem cells in the tumor population, the presence of ALDH1A1 protein in tumor cells was investigated. For distribution to immunohistochemical subtypes, the ER, PR, HER-2 / neu receptors, the expression of the Ki-67 protein and the expression of the NF-kB signaling molecules, PI3K PTEN, NOTCH, WNT, Hedgehog were also investigated in all cases. We used, an immunohistochemical method. Results. It was revealed that the ratio of cases of different immunohistochemical subtypes differs in the groups with low and high levels of tumor stem cells. At the same time, in the group with a high content of tumor stem cells, the cases of Hormone receptor-negative HER-2 positive and Triple negative subtypes prevail (46 and 37%, respectively). These subtypes are considered the most unfavorable for the prognosis and response to chemotherapy. At the same time, in 96% of cases of the Luminal A subtype and in 100% of the cases of the Luminal B subtype, tumor stem cells were detected in an insignificant number. The largest number of cases in which more than 10% of tumor stem cells were detected in the common pool of tumor cells were Hormone receptor negative HER-2 positive (20%), Hormone receptor positive HER-2 positive (12%) and Triple negative subtypes (17%), while in the last group all cases with a high level of expression of ALDH1A1 contained more than 50% of tumor stem cells in the total pool of tumor cells. The redistribution of signaling pathways was detected in cases of Triple Negative and Hormone receptor negative HER2 positive subtypes with high and low content of cells expressing ALDH1A1. Conclusion. As a result of the study, it was found that the ratio of cases of different immunohistochemical subtypes differs in the groups with low and high levels of tumor stem cells. At the same time, in the group with a high content of tumor stem cells, the cases of Hormone receptor-negative HER-2 positive and Triple negative subtypes prevail. The study revealed the distribution of the signaling pathways NF-kB, PI3K PTEN, NOTCH, WNT, Hedgehog in the Triple Negative and Hormone receptor negative HER2 positive immunohistochemical subtypes. The distribution of signaling pathways varies depending on the presence or absence of cells with high ALDH1A1 expression.

Keywords: breast cancer, cancer stem cells, ALDH1A1, NF-kB, PI3K PTEN, NOTCH, WNT, Hedgehog

There is no conflict of interest.

Contact details of the corresponding author:
Sergey V. Sazonov
prof-ssazonov@yandex.ru

Received 08.04.2019

For citation:
Brilliant A.A., Brilliant Y.M., Sazonov S.V., Denisenko S.A., Demidov S.M., Leontiev S.L. ALDH1A1 positive tumor cells and their effect on the signaling pathways of NF-Kb, PI3K PTEN, NOTCH, WNT, Hedgehog in cases of triple negative and hormone receptor negative HER2 positive immunohistochemical subtypes of breast cancer. Vestn. Ural. Med. Akad. Nauki. = Journal of Ural Medical Academic Science. 2019, Vol. 16, no. 1, pp. 41–49. DOI: 10.22138/2500-0918-2019-16-1-41-49 (In Russ)

REFERENCES:
1. Reya T. ,Morrison S.J., Carke M.F., et al. Stem cells,cancer, and cancer stem cells. Nature 2001; 414: 105-11.
2. Brilliant A.A., Brilliant Yu.M., Sazonov S.V. Characteristics of the relation between epithelial-mesenchymal transition and proliferative activity in breast carcinomas. European Journal of Cancer. 2013. V. 49. No. S2. p. 216.
3. Mnichovich, MV, Midiber, K.Yu., Gallyamova, A.R. and others. Immunohistochemical evaluation of expression of cadherin-catenin complex in breast cancer. Journal of Anatomy and Histopathology. 2017, No. 6 (1), pp. 63-68. (In Russ.)
4. Brilliant Yu.M., Brilliant A.A., Sazonov S.V. Epithelial cadherins and associated molecules in invasive lobular breast cancer. Archive of pathology. 2017, No. 1 (79), pp. 12-18. (In Russ.)
5. Sazonov S.V., Brilliant A.A., Brilliant Yu.M. Relationship of proliferative processes and features of the receptor apparatus of breast carcinoma tumor cells. Genes and cells. 2017, 12 (4), 76-81. (In Russ.)
6. Zasadkevich Yu.M., Sazonov S.V. The role of the cell adhesion molecule of E-cadherin in human ontogenesis is normal and pathological. Morphology. 2014, 5 (146), 78-82. (In Russ.)
7. Zasadkevich Yu.M., Brilliant A.A., Sazonov S.V. The role of cadherin in normal and in the development of breast cancer. Archive of pathology. 2015, No. 3 (77), pp. 57-64. (In Russ.)
8. Collins A.T., Berry P.A., Hyde C., et al. Prospective identification of tumorigenic prostate cancer stem cells. NJCancer Res. 2005; 65(23):10946-51.
9. Jinesh G., Willis D.L., Kamat A.M. Bladder Cancer Stem Cells: Biological and Therapeutic Perspectives. Current Stem Cell Research & Therapy 2014; 9(2):1-13.
10. Al-Hajj M., Wicha M.S., Benito-Hernandez A., et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–8.
11. Ginestier C., Hur M.H., Charafe-Jauffret E., et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007; 1: 555–67.
12. Pearce D.J., Taussig D., Simpson C., et al. Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples. Stem Cells 2005; 23(6):752-60.
13. Grebnev D.Yu., Maklakova I.Yu., Yastrebov A.P. The prospect of using stem cells to activate blood formation in conditions of age involution against the background of exposure to ionizing radiation. Successes of gerontology. 2014. Vol. 27. No. 2. P. 348-352. (In Russ.)
14. Ginestier C., Hur M.H., Charafe-Jauffret E., et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007; 1(5): 555–567.
15. Morimoto K., Kim S.J., Tanei T., et al. Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression. Cancer Sci. 2009; 100(6):1062-8.
16. Sazonov S.V., Leontyev S.L., Brilliant A.A. Experience of the reference laboratory for HER2 / neu testing of breast carcinoma in the Sverdlovsk region. Bulletin of the Ural Medical Academic Science. 2013. No. 1 (43). pp. 56-60. (In Russ.)
17. Brilliant A.A., Brilliant Yu.M., Sazonov S.V. Features of the ALDH1 + pool of tumor stem cells in immunohistochemical subtypes of invasive breast cancer. Bulletin of the Ural Medical Academic Science. 2018. T. 15. No. 3. Pp. 413-420. (In Russ.)
18. Sazonov S., Brilliant A., Brilliant Y. Proliferation of cancer stem cells in triple negative breast cancer. The Breast Journal, 2017, Vol. 32, Supp. 1: 29-30.
19. Semiglazov V.F., Paltuev R.M., Semiglazov V.V., Dashyan G.A., Semiglazova T.Y., Krivorotko P.V., Nikolaev K.S. General St. Gallen-2015 guidelines for the treatment of early breast cancer (adapted by the experts of the Russian Society of Breast Oncologists). Women Reproductive System Tumors. 2015;11(3):43-60. (In Russ.)

Authors
Aleksandr A. Brilliant
Institute of Medical Cell Technologies,
Cand.Sci. (Bio.), Senior Reseacher
Russin Federation, 620000, Vilonova str., 76a, Yekaterinburg
alex_brilliant@mail.ru

Yulia M. Brilliant
Institute of Medical Cell Technologies,
Cand.Sci. (Med.), Researcher
Russin Federation, 620000, Vilonova str., 76a, Yekaterinburg
yulkat@bk.ru

Sazonov Sergey V.
Ural State Medical University
Dr. Sci. (Med.), Professor, the Head of the Department of histology, cytology and embryology of Ural State Medical University, Head of the laboratory of 
pathomorphology of Institute of Medical Cell Technologies
Russin Federation, 620000, Vilonova str., 76a, Yekaterinburg
prof-ssazonov@yandex.ru

Svetlana A. Denisenko
Ural State Medical University
Cand. Sci. (Bio), Researcher
Russian Federation, 620028 Repina str.,3, Yekaterinburg
kiparis1983@mail.ru

Sergey M. Demidov
Government Budget Educational Organization «Ural State Medical University» of Ministry of Healthcare of Russian Federation
Dr. Sci. (Med.), Professor, the Head of the department of oncology
Russian Federation, 620028 Repina str.,3, Yekaterinburg
professordemidov@yandex.ru

Sergey L. Leontiev
Institute of Medical Cell Technologies,
Healthcare of Russian Federation
Dr. Sci. (Med.), Professor, the Head of Institute of Medical Cell Technologies

ls.04@yandex.ru

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)