Ceramide kinase confers tamoxifen resistance in estrogen receptor-positive breast cancer by altering sphingolipid metabolism

Pharmacol Res. 2023 Jan;187:106558. doi: 10.1016/j.phrs.2022.106558. Epub 2022 Nov 21.

Abstract

Dysregulated sphingolipid metabolism contributes to ER+ breast cancer progression and therapeutic response, whereas its underlying mechanism and contribution to tamoxifen resistance (TAMR) is unknown. Here, we establish sphingolipid metabolic enzyme CERK as a regulator of TAMR in breast cancer. Multi-omics analysis reveals an elevated CERK driven sphingolipid metabolic reprogramming in TAMR cells, while high CERK expression associates with worse patient prognosis in ER+ breast cancer. CERK overexpression confers tamoxifen resistance and promotes tumorigenicity in ER+ breast cancer cells. Knocking out CERK inhibits the orthotopic breast tumor growth of TAMR cells while rescuing their tamoxifen sensitivity. Mechanistically, the elevated EHF expression transcriptionally up-regulates CERK expression to prohibit tamoxifen-induced sphingolipid ceramide accumulation, which then inhibits tamoxifen-mediated repression on PI3K/AKT dependent cell proliferation and its driven p53/caspase-3 mediated apoptosis in TAMR cells. This work provides insight into the regulation of sphingolipid metabolism in tamoxifen resistance and identifies a potential therapeutic target for this disease.

Keywords: Breast cancer; CERK; Sphingolipid metabolism; Tamoxifen resistance.

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Breast Neoplasms* / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MCF-7 Cells
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptors, Estrogen / metabolism
  • Sphingolipids
  • Tamoxifen* / pharmacology
  • Tamoxifen* / therapeutic use

Substances

  • Tamoxifen
  • ceramide kinase
  • Receptors, Estrogen
  • Phosphatidylinositol 3-Kinases
  • Antineoplastic Agents, Hormonal
  • Sphingolipids