Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival

Cell Signal. 2017 Apr:32:85-92. doi: 10.1016/j.cellsig.2017.01.021. Epub 2017 Jan 17.

Abstract

About 40,000 American women die from metastatic breast cancer each year despite advancements in treatment. Approximately, 15% of breast cancers are triple-negative for estrogen receptor, progesterone receptor, and HER2. Triple-negative cancer is characterized by more aggressive, harder to treat with conventional approaches and having a greater possibility of recurrence. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid signaling mediator has emerged as a key regulatory molecule in breast cancer progression. Therefore, we investigated whether cytosolic sphingosine kinase type 1 (SphK1) and nuclear sphingosine kinase type 2 (SphK2), the enzymes that make S1P are critical for growth and PI3K/AKT, ERK-MAP kinase mediated survival signaling of lung metastatic variant LM2-4 breast cancer cells, generated from the parental triple-negative MDA-MB-231 human breast cancer cell line. Similar with previous report, SphKs/S1P signaling is critical for the growth and survival of estrogen receptor positive MCF-7 human breast cancer cells, was used as our study control. MDA-MB-231 did not show a significant effect of SphKs/S1P signaling on AKT, ERK, and p38 pathways. In contrast, LM2-4 cells that gained lung metastatic phenotype from primary MDA-MB-231 cells show a significant effect of SphKs/S1P signaling requirement on cell growth, survival, and cell motility. PF-543, a selective potent inhibitor of SphK1, attenuated epidermal growth factor (EGF)-mediated cell growth and survival signaling through inhibition of AKT, ERK, and p38 MAP kinase pathways mainly in LM2-4 cells but not in parental MDA-MB-231 human breast cancer cells. Moreover, K-145, a selective inhibitor of SphK2, markedly attenuated EGF-mediated cell growth and survival of LM2-4 cells. We believe this study highlights the importance of SphKs/S1P signaling in metastatic triple-negative breast cancers and targeted therapies.

Keywords: EGF; Proliferation; S1P; Signaling; SphKs; Sphingolipids; Triple-negative metastatic breast cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Down-Regulation / drug effects
  • Epidermal Growth Factor / pharmacology
  • Female
  • Humans
  • Lysophospholipids / metabolism*
  • Neoplasm Metastasis
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Triple Negative Breast Neoplasms / enzymology*
  • Triple Negative Breast Neoplasms / pathology*

Substances

  • Lysophospholipids
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • sphingosine 1-phosphate
  • Epidermal Growth Factor
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine