Atorvastatin Inhibits Breast Cancer Cells by Downregulating PTEN/AKT Pathway via Promoting Ras Homolog Family Member B (RhoB)

Biomed Res Int. 2019 Mar 18;2019:3235021. doi: 10.1155/2019/3235021. eCollection 2019.

Abstract

Background: Breast cancer (BC) is one of the most common malignant tumors in women around the world. Atorvastatin (ATO) was found to be associated with a decreased risk of recurrence and mortality in cancer. But the exact mechanism of its carcinostatic effects is unclear. The expression level of Ras homolog family member B (RhoB) in breast cancer cells was found to be upregulated after being treated with ATO. Thus, we conjecture that altered expression of RhoB induced by ATO may be decisive for the migration and progression of breast cancer.

Methods: The effects of ATO on breast tumor cells in vivo and in vitro were detected by clone formation assay, CCK-8 assay, flow cytometry, wound healing, transwell assays, tumor xenograft model, and immunohistochemistry. Distribution of RhoB in different breast cancer tissues and its influence on prognosis were analyzed using the data from TCGA or GEO databases. The relationship between RhoB and PTEN/AKT pathway was detected by Western blotting and RT-qPCR.

Results: ATO inhibits proliferation, invasion, EMT, and PTEN/AKT pathway and promotes apoptosis in breast tumor cells. In addition, ATO inhibits the volume and weight of breast tumor in tumor-bearing mice and upregulated RhoB in tumor tissues. The expression of RhoB in mRNA and protein level was upregulated in statin-treated breast cancer cells and downregulated in cancer tissues. Low expression of RhoB links with poor prognosis in patients with breast cancer (HR = 0.74[0.66-0.83], p =7e-8, log-rank test). Further research found that RhoB inhibits the proliferation, invasion, EMT, and PTEN/AKT signal pathway in breast tumor cells.

Conclusions: The exact mechanism of ATO's carcinostatic effects in breast cancer is related to downregulating PTEN/AKT pathway via promoting RhoB. Our study also demonstrates the potential applicability of RhoB as a therapeutic target for breast cancer.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Atorvastatin / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Down-Regulation / drug effects*
  • Down-Regulation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Recurrence, Local / genetics
  • PTEN Phosphohydrolase / genetics*
  • Prognosis
  • Proto-Oncogene Proteins c-akt / genetics*
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • Xenograft Model Antitumor Assays / methods
  • rhoB GTP-Binding Protein / genetics*

Substances

  • RHOB protein, human
  • Atorvastatin
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • rhoB GTP-Binding Protein