The LDHC-STAT3 Signaling Network Is a Key Regulator of Basal-like Breast Cancer Cell Survival

Adviti Naik1, Remy Thomas1, Martin Sikhondze1

  • 1Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha P.O. Box 34110, Qatar.

Cancers
|July 13, 2024
PubMed

Insights

Targeting lactate dehydrogenase C (LDHC) impacts breast cancer cell survival differently based on subtype. LDHC silencing harms basal-like breast cancer but aids Her2-enriched tumors, suggesting subtype-specific therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Breast cancer treatment advances include immunotherapy and targeted drugs, yet long-term efficacy with minimal side effects remains a challenge.
  • Cancer testis antigens (CTAs) present therapeutic opportunities due to tumor specificity and immunogenicity.
  • Lactate dehydrogenase C (LDHC) is implicated in genomic stability, and its targeting enhances responses to DNA damage response drugs in breast cancer.

Purpose of the Study:

  • To investigate the molecular mechanisms of LDHC silencing in different breast cancer subtypes.
  • To explore the role of the LDHC-STAT3 signaling axis in breast tumor cell survival.
  • To determine the potential of LDHC-targeted therapy and STAT3 inhibition for specific breast cancer subtypes.

Main Methods:

  • LDHC silencing was performed in basal-like (MDA-MB-468, BT-549) and Her2-enriched (HCC-1954) breast cancer cell lines.
  • Transcriptomic analyses were conducted to assess gene expression changes and pathway activation.
  • STAT3 signaling pathway activity was evaluated following LDHC depletion, with and without STAT3 inhibition.

Main Results:

  • LDHC silencing differentially affected STAT3 pathway activation in a cell line-dependent manner.
  • In basal-like breast cancer cells, LDHC silencing compromised survival and downregulated STAT3 signaling.
  • In Her2-enriched breast cancer cells, LDHC silencing enhanced STAT3 signaling and cell survival; STAT3 inhibition reversed this effect and showed single-agent anti-cancer activity.

Conclusions:

  • The LDHC-STAT3 signaling axis regulates breast tumor cell survival in a subtype-specific manner.
  • LDHC-targeted therapy may benefit basal-like breast cancer patients.
  • Her2-enriched breast cancer patients might benefit more from monotherapy with STAT3 inhibitors.

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