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The mTORC2 subunit RICTOR drives breast cancer progression by promoting ganglioside biosynthesis through

Mohammad Nafees Ansari1,2, Somesh K Jha3, Ali Khan1

  • 1Amity Institute of Integrative Sciences and Health, Amity University Haryana, Gurgaon, Haryana, India.

Plos Biology
|September 11, 2025
PubMed

Insights

RICTOR regulates sphingolipid and ganglioside synthesis in breast cancer by controlling UGCG expression via ZFX. This pathway promotes tumor growth and EGFR signaling, offering new therapeutic targets.

Area of Science:

  • Cellular signaling
  • Metabolic pathways
  • Cancer biology

Background:

  • Sphingolipids and gangliosides are vital in cell signaling and cancer progression.
  • Regulatory mechanisms of sphingolipid/ganglioside biosynthesis are not fully understood.

Purpose of the Study:

  • To investigate the role of RICTOR in regulating sphingolipid and ganglioside biosynthesis in breast cancer.
  • To elucidate the molecular mechanisms linking RICTOR to breast cancer progression.

Main Methods:

  • Utilized human breast cancer cell lines (MCF-7, BT-474).
  • Investigated transcriptional and epigenetic regulation by RICTOR.
  • Analyzed protein-DNA interactions and gene expression.
  • Validated findings in mouse models and clinical datasets (TCGA, METABRIC).

Main Results:

  • RICTOR regulates glucosylceramide and GD3 ganglioside synthesis by modulating UDP-Glucose Ceramide Glucosyl transferase (UGCG) expression.
  • Identified Zinc Finger protein X-linked (ZFX) as a RICTOR-responsive transcription factor involved in UGCG regulation.
  • RICTOR-ZFX-UGCG axis activates EGFR signaling, promoting tumor growth.
  • Elevated RICTOR, ZFX, and UGCG expression observed in human breast cancer tissues.

Conclusions:

  • Established a RICTOR-AKT-ZFX-UGCG-Ganglioside-EGFR-AKT regulatory circuit crucial for breast cancer progression.
  • RICTOR plays a significant role in controlling sphingolipid and ganglioside metabolism in breast cancer.
  • This pathway represents a potential therapeutic target for luminal breast cancer.

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