Co-Inhibition of tGLI1 and GP130 Using FDA-Approved Ketoconazole and Bazedoxifene Is Synergistic Against the Growth and Metastasis of HER2-Enriched and Triple-Negative Breast Cancers.

in Cells by Sara Manore, Chuling Zhuang, Mariana K Najjar, Grace L Wong, Shivani Bindal, Kounosuke Watabe, Jiayuh Lin, Hui-Wen Lo

TLDR

  • Co-targeting tGLI1 and IL-6R/GP130/STAT3 signaling pathways demonstrates synergistic effects against HER2-enriched breast cancer and TNBC.
  • Combination treatment with tGLI1 and GP130 inhibitors shows promise for reducing breast cancer proliferation and metastasis.

Abstract

Breast cancer stem cells (CSCs) are resistant to most cancer therapeutics and contribute to tumor recurrence and metastasis. Two breast CSC-promoting transcription factors, truncated glioma-associated oncogene homolog 1 (tGLI1) and signal transducer and activator of transcription 3 (STAT3), have been reported to be frequently co-expressed in HER2-enriched breast cancer and triple-negative breast cancer (TNBC), undergo protein-protein interactions for gene regulation and activation, and functionally cooperate to promote breast CSCs. STAT3 can be activated by activated interleukin-6 receptor/glycoprotein-130 (IL-6R/GP130). Co-targeting of tGLI1 and IL-6R/GP130 has not been investigated in breast cancer or any tumor type. Here, we report that tGLI1 and GP130 are co-overexpressed in the majority of HER2-enriched breast cancers and TNBCs at 53.8% and 44.4%, respectively. tGLI1+IL-6/IL-6R/GP130 signaling is frequently co-enriched and co-activated in HER2-enriched breast cancer and TNBC when compared to luminal subtypes. tGLI1+GP130 co-overexpression strongly promotes CSCs of HER2-enriched breast cancer and TNBC. FDA-approved tGLI1 inhibitor Ketoconazole and GP130 inhibitor Bazedoxifene synergize against breast cancer proliferation and CSC phenotypes in vitro and reduce TNBC tumor growth and metastatic burden in vivo. Our study demonstrates, for the first time, that co-targeting tGLI1 and IL-6R/GP130/STAT3 signaling pathways is synergistic against HER2-enriched breast cancer and TNBC, warranting future clinical investigations.

Overview

  • The study investigates the role of trunctated glioma-associated oncogene homolog 1 (tGLI1) and signal transducer and activator of transcription 3 (STAT3) in promoting breast cancer stem cells (CSCs) in HER2-enriched breast cancer and triple-negative breast cancer (TNBC).
  • The study aims to explore the synergistic effects of co-targeting tGLI1 and IL-6R/GP130/STAT3 signaling pathways in breast cancer and TNBC.
  • The study uses a combination of wet and dry lab experiments to investigate the role of tGLI1 and GP130 in breast cancer and TNBC, including in vitro and in vivo assays.

Comparative Analysis & Findings

  • Co-overexpression of tGLI1 and GP130 was found to be significantly higher in HER2-enriched breast cancer and TNBC compared to luminal breast cancer.
  • tGLI1 and GP130 signaling was found to be frequently co-enriched and co-activated in HER2-enriched breast cancer and TNBC.
  • Combination treatment with tGLI1 inhibitor Ketoconazole and GP130 inhibitor Bazedoxifene demonstrated synergistic effects against breast cancer proliferation and CSC phenotypes in vitro and reduced TNBC tumor growth and metastatic burden in vivo.

Implications and Future Directions

  • The study suggests that co-targeting tGLI1 and IL-6R/GP130/STAT3 signaling pathways may be a promising therapeutic strategy for HER2-enriched breast cancer and TNBC.
  • Future clinical investigations should explore the safety and efficacy of combined tGLI1 and IL-6R/GP130/STAT3 targeting therapy in breast cancer patients.
  • The study highlights the need for further investigation into the molecular mechanisms underlying the synergistic effects of combining tGLI1 and IL-6R/GP130/STAT3 targeting therapy.
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