The effect of the acetyl-amide form of the synthetic peptide HLDF-6 on the CDH2 and CD24 expression in breast cancer
https://doi.org/10.18699/SSMJ20250310
Abstract
The development and research of drugs capable of reducing the malignancy of tumors is one of the most promising areas in the differentiation therapy of breast cancer (BC). As the full-size differentiation factor (HLDF) significantly contributes to enhancing the differentiation level of invasive breast carcinoma cells of a non-specific type, it can be considered as a promising tool for differentiating therapy of BC. The disadvantage of full-size HLDF is its rapid biodegradation in the body. In this regard, the acetyl-amide form of the peptide (HLDF-6) was synthesized to protect against hydrolysis. However, the effect of this HLDF-6 on breast cancer cell differentiation remains unclear.
Aim of the study was to investigate the effect of the acetyl-amide form of the synthetic peptide HLDF-6 on the expression of CD24 and CDH2 clusters of differentiation in BC cells, taking into account differences in molecular genetic subtypes of the tumor.
Material and methods. The study was conducted on BC biopsies of 33 patients using the methods of tissue cultures and immunohistochemistry.
Results. It was found that the use of the acetyl-amide form of the synthetic peptide HLDF-6 leads to a decrease in the proportion of cells expressing CD24 and CDH2 in BC samples with luminal subtypes of breast cancer: luminal A (LA) and luminal B HER2-negative (LB). To a lesser extent, this effect was manifested in the study of samples of patients with triple negative subtype of breast cancer (TN). The results of the ROC analysis showed that CDH2 and CD24 molecules are significant predictors for evaluating the effect of stimulating the differentiation of low-grade breast cancer cells within various subtypes of BC.
Conclusions. The study indicates the prospects of using the acetyl-amide form of the synthetic peptide HLDF-6 for differentiating therapy in patients with LA and LB HER2-negative subtypes of BC.
Keywords
About the Authors
S. A. ArkhipovRussian Federation
Sergey A. Arkhipov, doctor of biological sciences
630091; Krasny ave., 52; 630117; Timakova st., 2; Novosibirsk
E. D. Mangazeeva
Russian Federation
Ekaterina D. Mangazeeva
630091; Krasny ave., 52; 630117; Timakova st., 2; Novosibirsk
V. V. Arkhipova
Russian Federation
Valentina V. Arkhipova
630091; Krasny ave., 52; Novosibirsk
A. P. Bogachuk
Russian Federation
Anna P. Bogachuk, candidate of chemical sciences
117997; Miklukho-Maklaya sr., 16/10; Moscow
V. M. Lipkin
Russian Federation
Valery M. Lipkin, doctor of chemical sciences, corresponding member of RAS
117997; Miklukho-Maklaya sr., 16/10; Moscow
A. I. Autenshlyus
Russian Federation
Alexander I. Autenshlyus, doctor of biological sciences, professor
630091; Krasny ave., 52; 630117; Timakova st., 2; Novosibirsk
References
1. Kawamata H., Tachibana M., Fujimori T., Imai Y. Differentiation-inducing therapy for solid. Curr. Pharm. Des. 2006;12(3):379–385. doi: 10.2174/138161206775201947
2. Yan M., Liu Q. Differentiation therapy: a promising strategy for cancer treatment. Chin. J. Cancer. 2016;35:3. doi: 10.1186/s40880-015-0059-x
3. Bar-Hai N., Ishay-Ronen D. Engaging plasticity: differentiation therapy in solid tumors. Front. Pharmacol. 2022;13:944773. doi: 10.3389/fphar.2022.944773
4. Fotinos J., Barberis L., Condat C.A. Effects of a differentiating therapy on cancer stem cell-driven tumors. J. Theor. Biol. 2023;572:111563. doi: 10.1016/j.jtbi.2023.111563
5. Zhu K., Xia Y., Tian X., He Y., Zhou J., Han R., Guo H., Song T., Chen L., Tian X.D. Characterization and therapeutic perspectives of differentiation-inducing therapy in malignant tumors. Front. Genet. 2023;14:1271381. doi: 10.3389/fgene.2023.1271381
6. Mukherjee S., Sen S., Adhikary S., Sengupta A., Mandal P., Dasgupta D., Chakrabarti P., Roy S., Das C. A novel role of tumor suppressor ZMYND8 in inducing differentiation of breast cancer cells through its dualhistone binding function. J. Biosci. 2020;45:2.
7. Ji H., Zhou Y., Zhuang X., Zhu Y., Wu Z., Lu Y., Li S., Zeng Y., Lu Q.R., Huo Y., Shi Y., Bu H. HDAC3 deficiency promotes liver cancer through a defect in H3K9ac/H3K9me3 transition. Cancer Res. 2019;79(14):3676–3688. doi: 10.1158/0008-5472.CAN-18-3767
8. Mody D., Bouckaert J., Savvides S.N., Gupta V. Rational design and development of HDAC inhibitors for breast cancer treatment. Curr. Pharm. Des. 2021;27(45):4610–4629. doi: 10.2174/1381612827666210917143953
9. Xu W.P., Zhang X., Xie W.F. Differentiation therapy for solid tumors. J. Dig. Dis. 2014;15(4):159–165. doi: 10.1111/1751-2980.12122
10. Bryan M., Pulte E.D., Toomey K.C., Pliner L., Pavlick A.C., Saunders T., Wieder R. A pilot phase II trial of all-trans retinoic acid (Vesanoid) and paclitaxel (Taxol) in patients with recurrent or metastatic breast cancer. Invest. New Drugs. 2011;29(6):1482–1487. doi: 10.1007/s10637-010-9478-3
11. Autenshlyus A.I., Zhurakovsky I.P., Davletova K.I., Bogachuk A.P., Lyakhovich V.V., Lipkin V.M. Influence of HLDF differentiation factor on nonspecific invasive breast carcinoma in vitro. Dokl. Biochem. Biophys. 2020;495(1):289–291. doi: 10.1134/S1607672920060010
12. Autenshlyus A.A., Zhurakovsky I.P., Marinkin I.O., Bogachuk A.P., Lipkin V.M. An agent that reduces the relative content of low-differentiated and increases the relative content of highly differentiated cells in invasive breast carcinoma of a non-specific type. Patent 2786528 RF; published 24. 02. 2021. [In Russian].
13. Rai H., Ahmed J. N-Cadherin: a marker of epithelial to mesenchymal transition in tumor progression. Intern. J. Oncol. 2014;10(1):1–8. ispub.com/IJO/ doi: 10/1/14796
14. Sung J.Y., Cheong J.H. Pan-cancer analysis reveals distinct metabolic reprogramming in different epithelial-mesenchymal transition activity states. Cancers (Basel). 2021;13(8):1778. doi: 10.3390/cancers13081778
15. Ku S.C., Liu H.L., Su C.Y., Yeh I.J., Yen M.C., Anuraga G., Ta H.D.K., Chiao C.C., Xuan D.T.M., Prayugo F.B., Wang W.J., Wang C.Y. Comprehensive analysis of prognostic significance of cadherin (CDH) gene family in breast cancer. Aging (Albany NY). 2022;14(20):8498–8567. doi: 10.18632/aging.204357
16. CD24. Pathology. Breast cancer. Human Protein Atlas. Available at: clck.ru/3M5LWg
17. Kristiansen G., Winzer K.J., Mayordomo E., Bellach J., Schluns K., Denkert C., Dahl E., Pilarsky C., Altevogt P., Guski H., Dietel M. CD24 expression is a new prognostic marker in breast cancer. Clin. Cancer Res. 2003;9(13):4906–4913.
18. Perelmuter V.M., Grigoryeva E.S., Savelieva O.E., Alifanov V.V., Andruhova E.S., Zavyalova M.V., Bragina O.D., Garbukov E.Yu., Menyailo M.E., Khozyainova A.A., … Tashireva L.A. EpCAM-CD24+ circulating cells associated with poor prognosis in breast cancer patients. Sci. Rep. 2024;14(1):12245. doi: 10.1038/s41598-024-61516-2
19. Rostoker R., Abelson S., Genkin I., Ben-Shmuel S., Sachidanandam R., Scheinman E.J., Bitton-Worms K., Shen Orr Z., Caspi A., Tzukerman M., LeRoith D. CD24(+) cells fuel rapid tumor growth and display high metastatic capacity. Breast Cancer Res. 2015;17(1):78. doi: 10.1186/s13058-015-0589-9
20. Tyulyandin S.A., Artamonova E.V., Zhigulev A.N., Koroleva I.A., Parokonnaya A.A., Semiglazova T.Yu., Stenina M.B., Frolova M.A. Breast cancer. Zlokachestvennyye opukholi = Malignant Tumors. 2023;13(3s2-1):157–200. [In Russian]. doi: 10.18027/2224-5057-2023-13-3s2-1-157-200
21. Neftel C., Laffy J., Filbin M.G., Hara T., Shore M.E., Rahme G.J., Richman A.R., Silverbush D., Shaw M.L., Hebert C.M. … Suva M.L. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell. 2019;178(4):835–849.e21. doi: 10.1016/j.cell.2019.06.024
22. Autenshlyus A.I., Studenikina A.A., Mikhaylova E.S., Proskura A.V., Varaksin N.A., Sidorov S.V., Bogachuk A.P., Lipkin V.M., Lyakhovich V.V. Influence of the HLDF differentiation factor on the production of cytokines by bio-tissues of breast tissue in its non-malignant diseases and in invasive carcinoma of a non-specific type. Biomeditsinskaya khimiya = Biomedical Chemistry. 2020;66(6):485–493. [In Russian]. doi: 10.18097/PBMC20206606485
23. Yang Y., Zhu G., Yang L., Yang Y. Targeting CD24 as a novel immunotherapy for solid cancers. Cell Commun. Signal. 2023;21(1):312. doi: 10.1186/s12964-023-01315-w
24. Creative Proteomix. Cytokine Proteomix. Luminex Cytokine Multiplex Panels Brochure. Exploring the PI3K-Akt Pathway and Cytokine Interactions with Luminex xMAP Technology. Available at: clck.ru/3M5LT2
25. Ni X., Hu G., Cai X. The success and the challenge of all-trans retinoic acid in the treatment of cancer. Crit. Rev. Food Sci. Nutr. 2019;59(sup1):S71–S80. doi: 10.1080/10408398.2018.1509201