Abstract
Background
Tamoxifen (Tam) is an effective treatment for estrogen receptor (ER) positive breast cancer. However, a significant proportion of patients develop resistance under treatment, presenting a therapeutic challenge. The study aims to determine the role of early growth response protein (EGR) 3 in tamoxifen resistance (TamR) and elucidate its molecular mechanism.
Methods
TamR cell models were established and NGS was used to screening signaling alternation. Western blot and qRT-PCR were used to analysis the expression of ERα, EGR3, MCL1 and factors associated with apoptosis. CCK8, colony formation and apoptosis assay were used to analysis resistance to Tam. Immunofluorescence, chromatin immunoprecipitation, and dual luciferase assays were used to investigate mechanism of regulation.
Results
We observed that EGR3, a deeply rooted ERα response factor, showed increased upregulation in response to both estrone (E1) and Tam in TamR cells with elevated level of E1 and ERα expression, indicating a potential connection between EGR3 and TamR. Mechanically, manipulating EGR3 expression revealed that it imparted resistance to Tam through increased expression of the downstream molecule MCL1 (apoptosis suppressor gene) that it regulated. Mechanismly, EGR3 directly binds to the promoter of the anti-apoptotic factor MCL1 gene, facilitating its transcription. Furthermore, apoptosis assays revealed that E1 reduces Tam induced apoptosis by upregulating EGR3 expression. Importantly, clinical public database confirmed the high expression of EGR3 in breast cancer tissue and in Tam-treated patients.
Conclusions
These findings shed light on the novel estrogen/EGR3/MCL1 axis and its role in inducing TamR in ER positive breast cancer. EGR3 emerges as a promising target to overcome TamR. The elucidation of this mechanism holds potential for the development of new therapeutic modalities to overcome endocrine therapy resistance in clinical settings.
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Data availability
Data will be made available on request.
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Funding
This study was supported by the Natural Science Foundation of China (nos. 31770968 and 31800661), the Science Fund Project of Tianjin (nos. 21JCYBJC00240 and 20JCYBJC01130).
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YX: investigation, data curation, conceptualization, original draft. XH: cell model establishment. JY: experiment assistance. MY & YY & JQ & LL: review and editing. YW: project administration, funding acquisition, review and editing.
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Xie, Y., Han, X., Yu, J. et al. EGR3 and estrone are involved in the tamoxifen resistance and progression of breast cancer. J Cancer Res Clin Oncol 149, 18103–18117 (2023). https://doi.org/10.1007/s00432-023-05503-6
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DOI: https://doi.org/10.1007/s00432-023-05503-6