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  3. Pharmacotranscriptomic profiling of resistant triple-negative breast cancer cells treated with lapatinib and berberine shows upregulation of PI3K/Akt signaling under cytotoxic stress

Pharmacotranscriptomic profiling of resistant triple-negative breast cancer cells treated with lapatinib and berberine shows upregulation of PI3K/Akt signaling under cytotoxic stress

  • Gene. 2022 Mar 30;816:146171. doi: 10.1016/j.gene.2021.146171.
Parham Jabbarzadeh Kaboli 1,  Shuang Luo 2,  Yao Chen 3,  Masume Jomhori 4,  Saber Imani 5,  Shixin Xiang 3,  Zhigui Wu 6,  Mingxing Li 3,  Jing Shen 3,  Yueshui Zhao 3,  Xu Wu 3,  Chi Hin Cho 3,  Zhangang Xiao 7
Affiliations

Affiliations

  • 1 Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, PR China; Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung, Taiwan, ROC. Electronic address: dr.parham@mail.cmu.edu.tw.
  • 2 Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, PR China.
  • 3 Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, PR China; South Sichuan Institution for Translational Medicine, Luzhou 646000, Sichuan, PR China.
  • 4 Department of Biotechnology Research, Razi Vaccine and Serum Research Institute, Mashhad, Iran.
  • 5 Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, PR China.
  • 6 Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, PR China; South Sichuan Institution for Translational Medicine, Luzhou 646000, Sichuan, PR China; Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan, PR China.
  • 7 Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, PR China; South Sichuan Institution for Translational Medicine, Luzhou 646000, Sichuan, PR China. Electronic address: xzg555898@hotmail.com.
PMID: 35026293 DOI: 10.1016/j.gene.2021.146171
Abstract

Triple-negative breast Cancer (TNBC) is the most incurable type of breast Cancer, accounting for 15-20% of breast Cancer cases. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and Her2, and berberine (BBR) is a plant-based alkaloid suggested to inhibit several Cancer signaling pathways. We previously reported that lapatinib activates the Akt oncoprotein in MDA-MB231 TNBC cells. The present study determined the mechanism(s) of Akt activation in response to lapatinib, BBR, and capivasertib (Akt Inhibitor) as well as the role of Akt signaling in chemoresistance in TNBC cells. Genetic profiles of 10 TNBC cell lines and patients were analyzed using datasets obtained from Gene Expression Omnibus and The Cancer Genome Atlas Database. Then, the effects of lapatinib, BBR, and capivasertib on treated MDA-MB231 and MCF-7 cell lines were studied using cytotoxicity, immunoblot, and RNA-sequencing analyses. For further confirmation, we also performed Real-Time PCR for genes associated with PI3K signaling. MDA-MB231 and MCF-7 cell lines were both strongly resistant to capivasertib largely due to significant Akt activation in both breast Cancer cell lines, while lapatinib and BBR only enhanced Akt signaling in MDA-MB231 cells. Next-generation Sequencing, functional enrichment analysis, and immunoblot revealed downregulation of CDK6 and DNMT1 in response to lapatinib and BBR lead to a decrease in cell proliferation. Expression of placental, Fibroblast Growth Factor, and angiogenic biomarker genes, which are significantly associated with Akt activation and/or dormancy in breast Cancer cells, was significantly upregulated in TNBC cells treated with lapatinib and BBR. Lapatinib and BBR activate Akt through upregulation of alternative signaling, which lead to chemoresistance in TNBC cell. In addition, lapatinib overexpresses genes related to PI3K signaling in resistant TNBC cell model.

Keywords

Akt; Berberine; Chemoresistance; Lapatinib; PI3K; Triple-negative breast cancer.

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