https://orcid.org/0000-0002-2404-0408
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Abstract
Background
Tamoxifen is the cornerstone of adjuvant therapy for hormone receptor-positive breast cancer. Despite its efficacy, limited drug sensitivity and endocrine resistance remain the important clinical challenges. The main objective of this study was to investigate fatostatin, which was found to sensitize breast cancer to the antitumour effect of tamoxifen both in vitro and in vivo.
Methods
Fatostatin-induced ER degradation was detected by immunoprecipitation assay. The antitumour effect of fatostatin and tamoxifen on MCF-7 and T47D cells was assessed by MTT and colony forming assays. Cell cycle arrest was detected by flow cytometric analysis. Apoptosis was detected by annexin V/propidium iodide double staining and TUNEL assay. Autophagy was detected by MDC assay and acridine orange staining. Migration and invasion assays were performed using a Transwell system, and the efficacy of the synergistic use of fatostatin and tamoxifen in vivo was evaluated using an MCF-7 xenograft model in BALB/c nu/nu female mice.
Results
The synergistic use of fatostatin and tamoxifen significantly suppressed cell viability and invasion, induced cell cycle arrest, and regulated apoptosis and autophagy in MCF-7 and T47D cell lines via PI3K-AKT-mTOR signalling. Additionally, the expression levels of Atg7/12/13, beclin and LC3B increased while p-mTOR and P62 expression levels decreased after treatment with fatostatin and tamoxifen. Tumor growth in the xenograft model was suppressed significantly with the synergistic treatment of fatostatin and tamoxifen.
Conclusion
Fatostatin could induce ER degradation by K48-linked polyubiquitination, which was the key mechanism contributing to tamoxifen inhibition of PI3K-AKT-mTOR signalling in breast cancer. Fatostatin may have a promising clinical use for ER-positive breast cancer patients.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 81502285, No. 81972475, No. 81874119, No. 81672613), National Key R&D Program of China (No. 2018YFC0114705), China Postdoctoral Science Foundation (No. 2018M630787, No. 2019T120593), Key Research and Development Program of Shandong Province (No. 2019GSF108140) and Special Support Plan for National High Level Talents (Ten Thousand Talents Program).
Study Approval
All animal experiments were performed with the approval of the Ethics Committee on Scientific Research of Qilu Hospital, Shandong University. All experimental procedures and protocols were reviewed and approved by the Animal Care and Use Committee of Qilu Hospital of Shandong University and were in accordance with the Guide for the Care and Use of Laboratory Animals.
Disclosure
The authors declare no conflicts of interest for this work.