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Registration Number

0225U004117, (0124U004351) , R & D reports

Title

Elucidation of functional relationships between isoforms of estrogen receptor ERα and isoforms of ribosomal protein kinase S6 (S6K1) in human breast carcinoma cells of different molecular subtypes

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Дослідження зв'язку між експресією та активністю ізоформ S6K1 та її N-кінцевих пептидів і регуляцією активності/експресії ядерної та мембранної форм та ERα, експресією ERα-залежних генів, генів ЕМТ та пов’язаними з цим змінами ключових фенотипових ознак ракових клітин.

Head

Filonenko Valerii V., Доктор біологічних наук

Registration Date

12-11-2025

Organization

Institute of Molecular Biology and Genetics of NAS of Ukraine

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The goal of the project is to determine the molecular regulatory relationships between isoforms of the estrogen receptor ERα and S6K1 kinase in human breast carcinoma cells of different molecular subtypes at the levels of regulation of their expression and activity and evaluate their role in the regulation of the transcriptome of genes associated with tumor progression, manifestations of key features of malignant cells and the effectiveness of tumor formation and metastases in model animals

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The main goal of the project is to determine the role of different ESR1 and S6K1 isoforms in the development of resistance of breast tumors to antiestrogen therapy. The main task of the project is to elucidate the molecular regulatory relationships between the estrogen receptor isoforms ERα and the ribosomal protein kinase S6 - S6K1 in human breast carcinoma cells of different molecular subtypes. To accomplish this task, several model sublines of human breast carcinoma cells of different molecular subtypes with differential and restored expression of different S6K1 isoforms were studied. Using the created sublines, convincing evidence was obtained for the first time that negative regulation of ESR1 gene expression by S6K1 isoforms occurs at the level of DNA transcription due to methylation of the gene promoter. It has been established that the leading role in the initiation of EMT is played by the activation of the expression of a new splice mRNA S6K1, which has an additional exon 1a, is translated simultaneously from two starts and thereby ensures the expression of the p60 isoform of S6K1, which is devoid of the N-terminal region and N-terminal regulatory peptides. Initiation of EMT occurs only in the case of simultaneous expression of both the p60 isoform of S6K1 and the N-terminal isoforms of S6K1. It has been established that the S6K1 isoforms differ in their functional activity in MCF-7 and MDA-MB-231 cells, which belong to different molecular subtypes. Further study of these forms of S6K1 is extremely relevant, because according to our data, it is precisely with the expression of the p60 isoform of the kinase that the initiation of epithelial-mesenchymal transition in human breast carcinoma MCF-7 cells is associated, which is an integral feature of malignant, invasive, with signs of metastasis tumors, which is also accompanied by suppression of ESR1 expression, which is a sign of the development of resistance to antiestrogen therapy..

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Garifulin Oleg Minirovich
Savins'ka Liliya Oleksiivna
Krups'ka Iryna V.
Martsyniuk Marko Ye.
Sergii Palchevskyi
Mykola Yatsenko

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2025-11-12