Napabucasin Attenuates Resistance of Breast Cancer Cells to Tamoxifen by Reducing Stem Cell-Like Properties

Abstract

Departmental sources Background: Tamoxifen (TAM) is the first-line drug for estrogen receptor-positive (ER+) breast cancer (BC) treatment. However, its resistance is a main obstacle in clinical practice. Thus, new therapeutic agents are urgently needed to fight TAM resistance. Material/Methods: Here, we constructed TAM-resistant ER+BC cells with TAM resistance, named MCF-7-R. Western blot, quantitative real-time PCR (qRT-PCR), ALDH1 activity analysis, and spheroid-forming detection were used to detect the stemness of cells and the effects of napabucasin (NP) on BC cell stemness. Cell counting kit-8 (CCK8) assay was used to evaluate the effects of NP on cell viability. Results: MCF-7-R cells exhibited higher stemness compared with the parental MCF-7 cells, which was evident by the increased spheroid formation ability at diluted concentration, aldehyde dehydrogenase (ALDH) activity, and expression of stemness critical biomarkers (Oct4, Nanog, and Sox2). Additionally, it was found that napabucasin (NP) specifically killed MCF-7-T cells, characterized by remarkably decreased IC 50 value. Notably, NP reduced MCF-7-R cell stemness, which was evident as the decreased stemness marker expression, spheroid-forming capacity, and ALDH1 activity. Importantly, NP attenuated TAM resistance of MCF-7-R cells and enhanced sensitivity of MCF-7 cells to TAM. Mechanistic study showed that NP inhibited STAT3 activation, and overexpression of STAT3 rescued NP-mediated inhibition of the stemness-like characteristics of MCF-7-R cells. Conclusions: NP might be used as an adjuvant therapy for ER+ BC patients with TAM resistance.

ElevatedCRB3 expression suppresses breast cancer stemness by inhibiting β‐catenin signalling to restore tamoxifen sensitivity

“…Altogether, decreased expression of the CRB3 gene activated the Wnt signalling pathway, resulting in the non‐tumorigenic, immortalized breast epithelial cell line MCF 10A acquiring cancer stem cell (CSC) properties . It has been postulated that tamoxifen resistance is attributed to the expansion of cancer stem cells . Thus, we in this study sought to investigate whether CRB3 could restore tamoxifen sensitivity of breast cancer cells by suppressing CSC properties via blocking the Wnt signalling pathway.…”

“…11 It has been postulated that tamoxifen resistance is attributed to the expansion of cancer stem cells. [12][13][14] Thus, we in this study sought to investigate whether CRB3 could restore tamoxifen sensitivity of breast cancer cells by suppressing CSC properties via blocking the Wnt signalling pathway.…”

The Anticancer Effect of Napabucasin (BBI608), a Natural Naphthoquinone

“…One example is in MCF7/MCF7-R breast cancer cells with tamoxifen resistance. Behaving as the canonical STAT3 inhibitor, napabucasin attenuated the stemness of breast cancer stemness [32] and another type of cancer [30] and decreased stemness marker expression, colony formation ability, and aldehyde dehydrogenase (ALDH) activity of MCF7-R, which exhibited a higher stemness to MCF7 cells. As such, napabucasin reverses the tamoxifen resistance of MCF7/MCF7-R breast cancer cells and enhances its sensitivity toward tamoxifen [32].…”

“…Napabucasin inhibits cancer stemness mainly by inhibiting STAT3 and its target genes. Napabucasin kills cancer stem cells and decreases stem-cell-related biomarkers Nanog, SOX2, Oct4, CD90, Klf4, survivin, c-Myc, and β-catenin in liver cancer [9], breast cancer [32], prostate cancer [18], and so on. Napabucasin blocked the survival and self-renewal of cancer stem cells and inhibited their related proteins and gene expression in pharynx squamous cell carcinoma FaDu cells.…”

Drug Resistance in Metastatic Breast Cancer: Tumor Targeted Nanomedicine to the Rescue

“…Hydroxytyrosol affected the BCSCs sub-population with CD44 + /CD24 −/low and ALDH1 activity by targeting the Wnt/β-catenin and TGF pathways (30460610). The combination of tamoxifen with napabucasin decreased stemness and rendered the cells sensitive to treatment by inhibiting signal transducers and activators of transcription 3 (STAT3) activation [ 82 ]. Iadademstat inhibited the formation of mammospheres induced by BCSCs in different breast cancer cell lines and patient derived xenografts [ 83 ].…”