Hypoxia‑induced exosomal CAMTA1 promotes radio‑resistance in MDA‑MB‑231 cells by regulating NRG1 to mediate M2 macrophage polarization

Li,Qian; Jiang,Minghua; Zhu,Biqing; Wei,Wei; Xia,Lei; Huang,Jian; Gao,Han; Du,Mingyu

doi:10.3892/ijo.2026.5875

May-2026 Volume 68 Issue 5

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May-2026 Volume 68 Issue 5

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Hypoxia‑induced exosomal CAMTA1 promotes radio‑resistance in MDA‑MB‑231 cells by regulating NRG1 to mediate M2 macrophage polarization

Authors:
- Qian Li
- Minghua Jiang
- Biqing Zhu
- Wei Wei
- Lei Xia
- Jian Huang
- Han Gao
- Mingyu Du
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Affiliations: Department of Radiation Oncology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China, Department of General Surgery, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China, Department of Pathology, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China

Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 62
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Published online on: March 20, 2026

https://doi.org/10.3892/ijo.2026.5875
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Abstract

Radiotherapy remains an irreplaceable treatment modality for breast cancer (BC). Calmodulin‑binding Transcription Activator 1 (CAMTA1) has been implicated in tumor progression; however, its role in BC is unclear. The present study aimed to elucidate the mechanistic function of CAMTA1 in BC. RNA sequencing was performed on RAW264.7 macrophages co‑cultured with 4T1 cells and subjected to X‑ray irradiation. In vitro, THP‑1 cells were co‑cultured with MDA‑MB‑231 cells under hypoxic conditions. Exosome morphology was observed under transmission electron microscopy and PKH67 staining was used to trace exosome uptake. Flow cytometry was used to detect CD163 expression while ELISA measured the levels of IL‑10 and IL‑12. Reverse transcription‑quantitative (RT‑q) PCR and immunoblotting analysis were used to detect the expressions of neuregulin 1 (NRG1), CAMTA1 and hypoxia‑inducible factor‑1α. Cell apoptosis, cell cycle distribution, cell viability and proliferation were evaluated using flow cytometry, MTT assay and colony formation assay. In vivo, transfected MDA‑MB‑231 cells were injected into BALB/c nude mice combined with radiotherapy and exosome injection. Histopathological changes in tumor tissues were examined using H&E staining. Immunohistochemistry analysis was performed to assess the expressions of NRG1, Caspase‑3 and CD163. RNA sequencing, RT‑qPCR and immunoblotting analysis revealed that NRG1 expression was markedly increased in RAW264.7 macrophages co‑cultured with 4T1 cells. NRG1 was found to be involved in M2 polarization induced by hypoxia‑treated MDA‑MB‑231 cells, which in turn promoted radio‑resistance. CAMTA1 expression was highly expressed in exosomes derived from hypoxic MDA‑MB‑231 cells and exosomal CAMTA1 promoted the M2 polarization of THP‑1 macrophages. In vivo, CAMTA1 overexpression greatly enhanced tumor growth, increased NRG1 expression, inhibited cell apoptosis and promoted M2 polarization of macrophages in tumor tissue. MDA‑MB‑231 cells were found to deliver CAMTA1 to macrophages via exosomes, leading to upregulation of NRG1 and induction of M2 polarization, thereby enhancing BC cells resistance to radiotherapy. These findings provided novel insights into the mechanisms underlying radio‑resistance in BC and identify exosomal CAMTA1 as a potential therapeutic target.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Hypoxia‑induced exosomal CAMTA1 promotes radio‑resistance in MDA‑MB‑231 cells by regulating NRG1 to mediate M2 macrophage polarization

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