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

Authors

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

Language

English

Publication Date

12-17-2024

Journal

Cells

DOI

10.3390/cells13242087

PMID

39768178

PMCID

PMC11674475

PubMedCentral® Posted Date

12-17-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Cytokine Receptor gp130, Female, Animals, Triple Negative Breast Neoplasms, Ketoconazole, Cell Line, Tumor, Indoles, Mice, Cell Proliferation, Neoplasm Metastasis, Drug Synergism, Erb-b2 Receptor Tyrosine Kinases, STAT3 Transcription Factor, Xenograft Model Antitumor Assays, Signal Transduction

Published Open-Access

yes

Recommended Citation

Manore, Sara; Zhuang, Chuling; Najjar, Mariana K; et al., "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" (2024). Faculty, Staff and Student Publications. 3507.
https://digitalcommons.library.tmc.edu/uthmed_docs/3507