Work

Tamoxifen and regulation of stress-induced senescence in breast cancer cells

Year: 2025

Type: article

Abstract: Introduction. Tumor cells are known not to undergo replicative aging – usually due to hyperactivation of telomerase, which restores telomere length during each cell division cycle. However, it is possible to induce aging in tumor cells through sublethal doses of cytostatics or irradiation – this is the so-called stress-induced or non-replicative senescence. Studying the mechanisms and regulatory pathways of this process is one of the important areas of modern oncology.Aim. To investigate the mechanisms of doxorubicin-induced senescence in different breast cancer cell subtypes and to explore possible approaches to regulating non-replicative aging.Materials and methods. The experiments were performed on in vitro cultured breast cancer cell lines MCF-7 and MDA-MB-231. Cellular senescence was assessed by β-galactosidase activity, morphological changes, and activation of the p53/p21 signaling pathway. Colorimetric assays, reporter analysis, and immunoblotting were used to evaluate the expression and activity of cellular proteins. DNA methyltransferase 3A (DNMT3A) knockdown was achieved using a standard lentiviral vector encoding antisense RNA against DNMT3A.Results. A potentiating effect of tamoxifen on doxorubicin-induced senescence – including in estrogen-independent breast cancer cells – was demonstrated. Enhanced non-replicative senescence was observed in resistant cells characterized by constitutive suppression of DNMT3A expression. For the first time, it was shown that DNMT3A suppression – either via decitabine treatment or DNMT3A knockdown – leads to an increase and maintenance of non-replicative senescence in MCF-7 cells.Conclusion. The findings indicate that non-replicative senescence in breast cancer cells can be enhanced and sustained in the presence of the antiestrogen tamoxifen, and underscore the key role of DNMT3A in regulating doxorubicin-induced senescence.

Source: Advances in molecular oncology

DOI: 10.17650/2313-805x-2025-12-3-46-56