Anti‐cancer stem cell activity of a hedgehog inhibitor GANT61 in estrogen receptor‐positive breast cancer cells

Abstract

Estradiol (E2) increases not only the cell growth but also the cancer stem cell (CSC) proportion in estrogen receptor (ER)‐positive breast cancer cells. It has been suggested that the non‐canonical hedgehog (Hh) pathway activated by E2 plays an important role in the regulation of CSC proportion in ER‐positive breast cancer cells. We studied anti‐CSC activity of a non‐canonical Hh inhibitor GANT61 in ER‐positive breast cancer cells. Effects of GANT61 on the cell growth, cell cycle progression, apoptosis and CSC proportion were investigated in four ER‐positive breast cancer cell lines. CSC proportion was measured using either the mammosphere assay or CD44/CD24 assay. Expression levels of pivotal molecules in the Hh pathway were measured. Combined effects of GANT61 with antiestrogens on the anti‐cell growth and anti‐CSC activities were investigated. E2 significantly increased the cell growth and CSC proportion in all ER‐positive cell lines. E2 increased the expression levels of glioma‐associated oncogene (GLI) 1 and/or GLI2. GANT61 decreased the cell growth in association with a G1‐S cell cycle retardation and increased apoptosis. GANT61 decreased the E2‐induced CSC proportion measured by the mammosphere assay in all cell lines. Antiestrogens also decreased the E2‐induced cell growth and CSC proportion. Combined treatments of GANT61 with antiestrogens additively enhanced anti‐cell growth and/or anti‐CSC activities in some ER‐positive cell lines. In conclusion, the non‐canonical Hh inhibitor GANT61 inhibited not only the cell growth but also the CSC proportion increased by E2 in ER‐positive breast cancer cells. GANT61 enhanced anti‐cell growth and/or anti‐CSC activities of antiestrogens in ER‐positive cell lines.

Characterization of the stemness potency of mammospheres isolated from the breast cancer cell lines

“…48 Estrogen stimulates CSCs activity and expands BCSCs in the ER+cells. 49,50 So, it seems that this model is more compatible with the hormone receptor positive breast cancer cell lines, which should be confirmed with an appropriate animal model and further studies in the future work.…”

Breast cancer lung metastasis: Molecular biology and therapeutic implications

“…Inhibitors against Wnt and Hh signaling are under preclinical and clinical tests for TNBC treatment. [163][164][165] Some genomics-based studies continue to shed light on the molecular understanding of TNBC tumorigenesis and heterogeneity and may provide implications for developing TNBCtargeted therapies. [166][167][168][169] Of note, Bartholomeusz et al found that the MEK inhibitor selumetinib inhibits and prevents lung metastasis of TNBC in xenograft models, 170 suggesting that MAPK pathway could be a potential therapeutic target for preventing TNBC lung metastasis.…”

Bioinformatics Studies Provide Insight into Possible Target and Mechanisms of Action of Nobiletin against Cancer Stem Cells

“…A previous study also showed functional interaction between estrogen and Wnt/ß-catenin signaling (Kouzmenko et al, 2004). Estradiol not only stimulates the estrogen signaling pathway but also increases the cancer stem cell (CSC) population in estrogen receptor-positive breast cancer cells (Kurebayashi et al, 2017). Treatment with hormone antagonist in estrogen receptor-positive breast cancer cells may repress their estrogen receptors and be resistant to hormone therapy (Simoes et al, 2015).…”