Drug Design, Development and Therapy (Aug 2020)

Fatostatin in Combination with Tamoxifen Induces Synergistic Inhibition in ER-Positive Breast Cancer

  • Liu Y,
  • Zhang N,
  • Zhang H,
  • Wang L,
  • Duan Y,
  • Wang X,
  • Chen T,
  • Liang Y,
  • Li Y,
  • Song X,
  • Li C,
  • Han D,
  • Chen B,
  • Zhao W,
  • Yang Q

Journal volume & issue
Vol. Volume 14
pp. 3535 – 3545

Abstract

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Ying Liu,1,* Ning Zhang,1,* Hanwen Zhang,1 Lijuan Wang,2 Yi Duan,1 Xiaolong Wang,1 Tong Chen,1 Yiran Liang,1 Yaming Li,1 Xiaojin Song,1 Chen Li,1 Dianwen Han,1 Bing Chen,2 Wenjing Zhao,2 Qifeng Yang1,2 1Department of Breast Surgery, Qilu Hospital of Shandong University, Ji’nan, Shandong, People’s Republic of China; 2Pathology Tissue Bank, Qilu Hospital of Shandong University, Ji’nan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qifeng Yang Email [email protected]: 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.Keywords: tamoxifen, fatostatin, oestrogen-positive breast cancer, polyubiquitination

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