Keywords
ultrastructure
receptor subtypes
How to Cite
Abstract
The structural and functional state of breast cancer tumor cells (TC) in groups of primary patients with different molecular subtypes of cancer was studied. In 75 primary patients with breast cancer, the receptor status of the tumor and the proliferative activity index Ki-67 were determined by the immunohistochemical method. Patients were divided into the following 6 groups: triple negative cancer, HER-2, RE, RE + RP, RE + HER-2 positive subtypes of cancer and three times positive cancer. Using standard methods of electron microscopy, the ultrastructure (US) of TC was investigated. It has been established that the US of the TC of the non-luminal breast cancer subtypes is predominantly characterized by large (possibly polyploid) undifferentiated forms with large, often pleiomorphic nuclei (PMN), whose function is growth and division, which corresponds to a high level of Ki-67, as well as a high incidence of PMN and phagosomes. For tumors with the expression of hormonal receptors, the most characteristic feature is the presence of intracellular lumens in the cytoplasm, which indicates a noticeable proteinsynthetic and secretory activity. RE-positive tumors have the lowest frequency of PMN and phagosomes, as well as the level of Ki-67, and a high frequency of intracellular lumens. In tumors of combined subtypes that do not have specific US signs, there is a mutual influence of hormonal receptors and HER-2 on the level of fission processes, the frequency of PMN and the ratio of nuclei of different sizes, obviously, due to the competition of hormonal receptors and HER-2 for targets that switch the functional activity of the cell or synthesis or division processes. Common to all the studied groups is the high heterogeneity of cell populations, in which, in addition to the characteristic for each of them, forms inherent in other subtypes are present. It has been established that each of the studied molecular subtypes has inherent characteristic US signs associated with the characteristics of their receptor status. A close correlation between the US indicators and proliferative activity was revealed. The heterogeneity of the TC population is observed in each of the studied cases. Co-expression of two to three receptors significantly modifies the studied parameters. The stages of the formation of intracellular gaps in the TC are illustrated.
Keywords: breast cancer, ultrastructure, receptor subtypes.
References
Ragimzade S.E. (2017). Rakmolochnoizhelezy: epidemiolohiia, faktory riska, patohenez, diahnostika [Breast cancer: epidemiology, risk factors, pathogenesis, diagnosis, prognosis].Mizhnarodnyi medychnyi zhurnal - International Medical Journal, issue 2, pp. 60-64. http://www.imj.kh.Ua/archive/2017/2/13.
Mykhailovych Yu.I., Zhurbenko A. V. (2016). Rakhrudnoi zalozy, realnaproblemadliavyrishennia na natsionalnomu rivni [Breast cancer is a real problem to be addressed nationally]. Ukrainskyi radiolohichnyi zhurnal - Ukrainian Radiological Journal, suppl. 1. XIII Congress of Oncologists and Radiologists of Ukraine (materials of the Congress) May 26-28, 2016, Kyiv, pp. 7-8. http://medradiologia.org.ua/assets/files/dodatok/dodat_2016_l.pdf.
Chen W, Hoffmann A.D., Lui H., Lui X. (2018). Organotropism new insights into molecular mechanisms of breast cancer metastasis. NPJPrecis. Oncol., vol. 2, № 1, p. 4. DOI: 10.1038/s41698-018-0047-0, PMID: 29872722, PMCID: PMC5871901.
Frank H.A., Danilova N.V, Andreieva Yu.Yu., Nefedova N.A. (2013). Klassifikatsiia opukholei molochnoi zhelezy VOZ 2012 hoda [2012 WHO Breast Tumor Classification], Arkhivpatolohii -Archive of Pathology, vol. 75, № 2, pp. 53-63. Retrieved from 2013/2/1000419552013021053 [in Russian], https://www.mediasphera.ru/issues/arkhiv-patologii/
Aleskandarany M.A., Vandenberghe M.E., Marchio C., Ellis I.O., Sapino A., Rakha E.A. (2018). Tumor heterogeneity of breast cancer: from morphology to personal medicine. Pathobiology, vol. 85, № 1-2, pp. 23-34. DOI: 10.1159/000477851, PMID: 29428954.
Hirata B.K.B., Oda J.M., Guembarovaki R.L., Ariza C.B., de Oliveira C.E.C., Watanabe M.A.E. (2014). Molecular markers for breast cancer: prediction on tumor behavior. Dis. Markers, vol. 2014, pp. 513158. DOI: 10.1155/2014/513158, PMID: 24591761, PMCID: PMC3925609.
Wang G.S., Zhu H., Bi S.J. (2012). Pathological feature and prognosis of different molecular subtypes of breast cancer. Mol. Med. Rep., vol. 6, № 4, pp. 779-782. DOI: 10.3892/mmr.2012.981, PMID: 22797840.
Haque M.M., Desai K.V (2019). Pathways to endocrine therapy resistance in breast cancer. Front. Endocrinol. (Lausanne), vol. 10, pp. 573. DOI: 10.3389/fendo.2019.00573, PMID: 31496995, PMCID: PMC6712962.
Pohlmann P.P., Mayer LA., Memaugh R. (2009). Resistance to Trastuzumab in breast cancer. Clin. Cancer Res., vol. 15, № 24, pp. 7479-7491. DOI: 10.1158/1078-0432.CCR-09-0636, PMID: 20008848, PMCID: PMC3471537.
Hrabovyi О.М., Zaretskyi Μ.В., Potorocha Ο.M., Antoniuk S.A., Velykoshapko A.D. (2011). Morfofunktsionalna heterohennist klityn pukhlyn yak pokaznyk yikh patohenetychnoho potentsialu [Morphofunctional heterogeneity of tumor cells as an indicator of their pathogenetic potential]. Klinicheskaia onkolohiia - Clinical Oncology, special issue II (XII zyizd onkolohiv Ukrainy, m. Sudak, Avtonomna Respublika Krym, 20-22 veresnia 2011 r. Materialy zyizdu - XII Congress of Oncologists of Ukraine, Sudak, Autonomous Republic of Crimea, September 20-22,2011. Proceedings of the Congress), pp. 20. Retrieved from [in Ukrainian], https://www.clinicaloncology.com.ua/wp/wp-content/uploads/2011/10/16-26.pdf
Harris J.R. (Eds.). (1991). Electron microscopy in biology. (In the practical approach series).
D. Richwood, B.D. Hames (Series ed.). N.Y.: Oxford University Press, 308 p. https://doi.org/10.1002/jemt. 1070220211.
Suslikov V.I. (1972). Maksimalno pravdopodobnaia otsenka dostovemosti razlichiia mezhdu rezultatami nabliudeniia, kohda ozhidaiemoie kolichestvo osobei s nalichiiem effekta ili yeho otsutstviiem v odnoi (ili neskolkikh) hruppe (hruppakh) menshe piati [The most plausible estimate of the reliability of the difference between the observation results when the expected number of individuals with the presence of an effect or its absence in one (or several) group(s) is less than five]. Proceedings from Tezisy dokladov 2-і Vsesoiuznoi konferentsii po farmakolohii protivoluchevykh preparatov (h. Moskva, 20—24 noiabria 1972 h.) - Abstracts of the 2nd All-Union conference on the pharmacology of antiradiation drugs (Moscow, November 20-24, 1972). Moscow: Institut biofiziki MZ SSSR, pp. 38. [in Russian],
Yang Z., Barnes C.J., Kumar R. (2004). Human epidermal growth factor receptor 2 status modulates receptor alpha in breast cancer cells. Clin. Cancer Res., vol. 10, № 11, pp. 3621-3628. DOI: 10.1158/1078-0432.CCR-0740-3, PMID: 15173068.
Fei E, Zhang D., Yang Z., Wang Sh., Wang X., Wu Zh. et al. (2015). The number of polyploid giant cancer cells and epithelial-mesenchymal transition-related proteins are associated with invasion and metastasis in human breast cancer. J. Exp. Clin. Cancer Res., vol. 34, article number 158. DOI: 10.1186/S13046-015-0277-8, PMID: 26702618, PMCID: PMC4690326.
Choudhary A., Zachek B., LeraR.F., Zasadil L.M., Lasek A., Denu R.A. et al. (2016). Identification of selective lead compounds for treatment of high-ploidy breast cancer. Mol. Cancer Ther, vol. 15, № 1, pp. 48-59. DOI: 10.1158/1535-7163.MCT-15-0527, PMID: 26586723, PMCID: PMC4707107.
Zhang S., Zhang D., Yang Z., Zhang X. (2016). Tumor budding, micropapillary pattern, and polyploidy giant cancer cells in colorectal cancer: current status and future prospects. Stem Cells Int., vol. 2016, article ID 4810734. DOI: 10.1155/2016/4810734, PMID: 27843459, PMCID: PMC5097820.
Sharma S., Zeng J.Y, Zuang C.M., Zhou Y.-Q., Yao H.-Р., Hu X. et al. (2013). Small-molecule inhibitor BMS-777607 induces breast cancer cell polyploidy with increased resistance to cytotoxic chemotherapy agents. Mol. Cancer Ther, vol. 12, № 5, pp. 725-736. DOI: 10.1158/1535-7163.MCT-12-1079, PMID: 23468529.
Herashchenko B.I., Salmina K., Erenpreisa E. (2016). Poliploidyzatsiiayak adaptyvna vidpovid і proiav rezystentnosti zloiakisnykh pukhlyn [Polyploidization as an adaptive response and manifestation of resistance of malignant tumors]. Ukrainskyi radiolohichnyi zhurnal- Ukrainian Radiological Journal, suppl. 1. (XIII zyizd onkolohiv ta radiolohiv Ukrainy, m. Kyiv, 26-28 travnia 2016 r. - XIII Congress of Oncologists and Radiologists of Ukraine, Kyiv, May 26-28, 2016), pp. 50. Retrieved from http://medradiologia.org.ua/assets/files/dodatok/dodat_20161 .pdf [in Ukrainian].
Bussolati G., Maletta E, Asioli S., Annaratone L., Sapino A., Marchio C. (2014). “To be or not to be in good shape”: diagnostic and clinical value of nuclear shape irregularities in thyroid and breast cancer. Proceedings from Schirmer E., de las Heras J. (Eds.). Cancer Biology and the Nuclear Envelope. Advances in Experimental Medicine and Biology, vol. 773. Springer, N.Y. (pp. 101-121). https://doi.org/10.1007/978-l-4899-8032-8_5.
Capo-chichi C.D., Cao K.Q., Smedberg J., Ganjei-Azar P, Godwin A.K., Xu X.-X. (2011). Loss of А-type lamin expression compromises nuclear envelope integrity in breast cancer. Chin. J. Cancer, vol. 30, № 6, pp. 415-425. DOI: 10.5732/cjc.010.10566, PMID: 21627864, PMCID: PMC3941915.
Muhammadnejad S., Muhammadnejad A., Haddadi M., Oghabian M., Mohagheghi M., Tirgari F. et al. (2013). Correlation of microvessel density with nuclear pleomorphism, mitotic count and vascular invasion in breast and prostate cancers at preclinical and clinical levels Asian. Рас. J. Cancer Prev., vol. 14, issue l, pp. 63-68. DOI: 10.7314/APJCP.2013.14.1.63.
Tsutsui S., Yasuda K., Higashi H. Tahara K., Sugita S., Eguchi H. et al. (2004). Prognostic implication ofp53 protein expression in relation to nuclear pleomorphism and the MIB-1 counts in breast cancer. Breast Cancer, vol. 11, № 2, pp. 160-168. DOI: 10.1007/BF02968296, PMID: 15550862.
Remy L. (1986). The intracellular lumen: origin, role and implication of a cytoplasmic neostructure. Biol. Cell, vol. 56, issue 2, pp. 97-105. DOI: 10.1111/j.l768-322x.l986.tb00446.x, PMID: 2941104.
Hordiienko V.M., Kozymitskii V.H. (1978). Ultrastruktura endokrinnoi sistemy [Endocrine system ultrastructure]. Kiev: Zdorovia, 288 p. [in Russian].
Lukashova O.P., Mikhanovskyi O.A., Slobodianiuk O.V. (2008). Ultrastruktura klityn adenokartsynomy tila matky pislia zastosuvannia riznykh skhem peredoperatsiinoho promenevoho ta khemopromenevoho likuvannia [Ultrastructure of uterine body adenocarcinoma cells after different protocols of pre-operative radiotion and chemotherapy]. Ukrainskyi radiolohichnyi zhurnal – Ukrainian Radiological Journal, vol. XVI, issue 2, pp. 163-170. Retrieved from assets/files/arch/2008/2/ρ 163_170.pdf [in Ukrainian], https://medradiologia.org.ua/
Lukashova O.P, Starikov V.I., Basylaishvili S.Yu., Bely A.N., Teslenko LN. (2016). Ultrastruktura nemelkokletochnoho гака lehkikh і okruzhaiuschikh yeho tkanei [Ultrastructure of Non-Small Cell Lung Cancer and the Surrounding Tissues]. Novosti khirurhii - Surgery News, vol. 24, № 2, pp. 162-169. DOI: 10.18484/2305-0047.2016.2.162 [in Russian],
Remy L., Marvaldi J. (1085). Origin of intracellular lumina in HT 29 colonic adenocarcinoma cell line. An ultrastructural study. Virchows Arch. B. Cell. Pathol. Incl. Mol. Pathol., vol. 48, № 2, pp. 145—153. DOI: 10.1007/BF02890123, PMID: 2859687.
Remy L., Verrier B., Michel-Bechet M., MazzellaE.,Athouel-HaonA.M. (1983). Thyroid follicular morphogenesis mechanism: organ culture of the fetal gland as an experimental approach. J. Ultrastruct. Res., vol. 82, issue 3, pp. 283-295. DOI: https://doi.org/10.1016/S0022-5320(83)80015-X.
Remy L., Chalvet C., Ripert J.P., Gerolami A. (1989). Intracellular lumina and bile canaliculi in rat hepatocytes in vitro - a cytochemical study. Acta Histochem., vol. 85, issue 1, pp. 87-92. DOI: 10.1016/S0065-1281(89)80103-5, PMID: 2540607.
Teppermen J., Teppermen H.M. (1989). Fiziolohiia obmena veschestv і endokrinnoi sistemy [Metabolic and endocrine physiology]. (V.I. Kandror, Trans.). Ya.I. Azhipa (Ed.). Moscow: Mir, 656 p. [in Russian].
Arena V, Pennacchia L, Vecchio F.M., Carbone A. (2019). ER-/PR+/HER2- breast cancer type shows the highest proliferative activity among all other combined phenotypes and is more common in young patients: Experience with 6643 breast cancer cases. Breast J., vol. 25, issue 3, pp. 381-385. DOI: 10.1111/tbj.13236, PMID: 30916428.
Chen J.Q., Russo P.A., Cooke C., Russo I.H., Russo J. (2007). ERbeta from mitochondria to nucleus during estrogen-induced neoplastic transformation of human breast epithelial cells and is involved in estrogen-induced synthesis of mitochondrial respiratory chain proteins. Biochim. Biophys. Acta, vol. 1773, issue 12, pp. 1732-1746. DOI: 10.1016/j.bbamcr.2007.05.008, PMID: 17604135.