title: Metastatic triple-negative breast cancer is dependent on SphKs/S1P signaling for growth and survival.
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.
authors.affiliation: Roswell Park Cancer Institute, Division of Breast Surgery, Department of Surgical Oncology, Department of Molecular and Cellular Biology, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Aparna
authors.initials: A
authors.lastname: Maiti
authors.affiliation: Roswell Park Cancer Institute, Division of Breast Surgery, Department of Surgical Oncology, Department of Molecular and Cellular Biology, Elm and Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Takabe
authors.affiliation: Roswell Park Cancer Institute, Division of Breast Surgery, Department of Surgical Oncology, Department of Molecular and Cellular Biology, Elm and Carlton Streets, Buffalo, NY 14263, USA. Electronic address: nitai.hait@roswellpark.org.
authors.forename: Nitai C
authors.initials: NC
authors.lastname: Hait
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D009362:Neoplasm Metastasis; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D000099157:Sphingosine Kinase
chemical_list: D004815:Epidermal Growth Factor; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate
keywords: EGF; Proliferation; S1P; Signaling; SphKs; Sphingolipids; Triple-negative metastatic breast cancer