STAT3/Snail Signaling and Progression of Hypoxia Tolerance in Breast Cancer Cells

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Olga E. Andreeva^1,a*#, Danila V. Sorokin^1,b#, Alexander M. Scherbakov^1,2,c, Svetlana V. Vinokurova^1,d, Pavel B. Kopnin^1,e, Nadezhda V. Elkina^1,f, Maria D. Fedorova^1,g, Alexey N. Katargin^1,h, Danila S. Elkin^1,i, and Mikhail A. Krasil’nikov^1,j*

¹Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, 115522 Moscow, Russia

²Gause Institute of New Antibiotics, 119021 Moscow, Russia

^* To whom correspondence should be addressed.

^# These authors contributed equally to the work.

Received: April 23, 2025; Revised: June 19, 2025; Accepted: June 28, 2025

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One of the hallmarks of malignant neoplasms is their ability to sustain growth under hypoxic conditions resulting from insufficient oxygenation of tumor tissues. Prolonged hypoxia is associated with the gradual adaptation of tumor cells to low oxygen levels, leading to the enhanced survival, increased metastatic potential, and development of resistance to anticancer therapies. The aim of this study was to investigate the mechanisms underlying adaptation of breast cancer cell to prolonged hypoxia and maintenance of the hypoxia-tolerant phenotype. Using long-term culturing under low oxygen conditions (1% O₂), we established hypoxia-adapted sublines of luminal (MCF-7) and triple-negative (MDA-MB-231) breast cancer cells, characterized by a stable growth in a hypoxic environment. The acquisition of hypoxia tolerance was accompanied by the activation of the HIF-1α-dependent transcription factor STAT3 and persistent overexpression of Snail, a key downstream effector of STAT3. The maintenance and stabilization of hypoxia-tolerant phenotype are mediated by miR-181a-2, which targets the STAT3/Snail signaling axis in the resistant cells. Analysis of DNA methylation status revealed no significant changes in the expression or activity of DNA methyltransferases (DNMTs) in the hypoxia-adapted cells. However, pharmacological inhibition of DNMTs using decitabine, as well as DNMT knockdown, increased cell sensitivity to hypoxia and partially reversed the hypoxia-resistant phenotype, which was accompanied by the activation of pro-apoptotic p53 signaling. In conclusion, our findings suggest that the acquired hypoxia tolerance in breast cancer cells is mediated, at least in part, by the activation of the miR-181a-2/STAT3/Snail signaling pathway. Furthermore, the use of demethylating agents may represent a promising therapeutic approach to targeting hypoxia-tolerant cancer cell populations.

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KEY WORDS: hypoxia, breast cancer, STAT3, Snail, methylation, miR-181a-2

DOI: 10.1134/S0006297925601315

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