Irreversible inhibition of estrogen receptor α signaling and the emergence of hormonal resistance in MCF7 breast cancer cells induced by DNA damage agents

Alexander M Scherbakov; Danila V Sorokin; Valeria E Razuvaeva; Yuri Yu Shchegolev; Olga E Andreeva; Diana I Salnikova; Timur I Fetisov; Olga A Vlasova; Kirill I Kirsanov; Margarita V Gudkova; Mikhail A Krasil'nikov

doi:10.3892/br.2024.1727

Irreversible inhibition of estrogen receptor α signaling and the emergence of hormonal resistance in MCF7 breast cancer cells induced by DNA damage agents

Biomed Rep. 2024 Jan 19;20(3):42. doi: 10.3892/br.2024.1727. eCollection 2024 Mar.

Authors

Alexander M Scherbakov^{1

2}, Danila V Sorokin^{1

2}, Valeria E Razuvaeva¹, Yuri Yu Shchegolev¹, Olga E Andreeva¹, Diana I Salnikova^{1

3}, Timur I Fetisov⁴, Olga A Vlasova⁴, Kirill I Kirsanov^{4

5}, Margarita V Gudkova¹, Mikhail A Krasil'nikov^{1

2}

Affiliations

¹ Department of Experimental Tumor Biology, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, The Ministry of Health of Russia, Moscow 115522, Russian Federation.
² Molecular Genetics Laboratory, Institute of Clinical Medicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603022, Russian Federation.
³ Laboratory of Chemical Transformations of Antibiotics, Gause Institute of New Antibiotics, Moscow 119021, Russian Federation.
⁴ Department of Chemical Carcinogenesis, Institute of Carcinogenesis, N.N. Blokhin National Medical Research Center of Oncology, The Ministry of Health of Russia, Moscow 115522, Russian Federation.
⁵ Institute of Medicine, Patrice Lumumba Peoples' Friendship University of Russia, Moscow 117198, Russian Federation.

Abstract

Combining chemotherapy and hormone therapy is a prevalent approach in breast cancer treatment. While the cytotoxic impact of numerous chemotherapy drugs stems from DNA damage, the exact role of these DNA alterations in modulating estrogen receptor α (ERα) machinery remains elusive. The present study aimed to analyze the impact of DNA damage agents on ERα signaling in breast cancer cells and assess the signaling pathways mediating the influence of DNA damage drugs on the ERα machinery. Cell viability was assessed using the MTT method, while the expression of signaling proteins was analyzed by immunoblotting. ERα activity in the cells treated with various drugs (17β-estradiol, tamoxifen, 5-fluorouracil) was assessed through reporter gene assays. In vitro experiments were conducted on MCF7 breast cancer cells subjected to varying durations of 5-fluorouracil (5-FU) treatment. Two distinct cell responses to 5-FU were identified based on the duration of the treatment. A singular dose of 5-FU induces pronounced DNA fragmentation, temporally suppressing ERα signaling while concurrently activating AKT phosphorylation. This suppression reverses upon 5-FU withdrawal, restoring normalcy within ten days. However, chronic 5-FU treatment led to the emergence of 5-FU-resistant cells with irreversible alterations in ERα signaling, resulting in partial hormonal resistance. These changes mirror those observed in cells subjected to UV-induced DNA damage, underscoring the pivotal role of DNA damage in shaping estrogen signaling alterations in breast cancer cells. In summary, the results of the present study suggested that the administration of DNA damage agents to cancer cells can trigger irreversible suppression of estrogen signaling, fostering the development of partial hormonal resistance. This outcome may ultimately impede the efficacy of combined or subsequent chemo- and hormone therapy strategies.

Keywords: 5-fluorouracil; DNA damage; breast cancer; estrogen receptor α; progression; resistance; tamoxifen; ultraviolet C irradiation.

Grants and funding

Funding: The present study was supported (grant no. 22-25-00368) by the Russian Scientific Foundation, (M.V.G., https://rscf.ru/project/22-25-00368/, accessed on November 24, 2023).