CSNK1G2 differently sensitizes tamoxifen-induced decrease in PI3K/AKT/mTOR/S6K and ERK signaling according to the estrogen receptor existence in breast cancer cells.

Anh Thu Nguyen Hoang,Kwang-Lae Hoe,Sook-Jeong Lee,Joe W Ramos

doi:10.1371/journal.pone.0246264

Anh Thu Nguyen Hoang, Kwang-Lae Hoe + Show 2 more

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https://doi.org/10.1371/journal.pone.0246264

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Abstract

Tamoxifen (TAM) is a selective estrogen receptor modulator used for breast cancer patients. Prolonged use of tamoxifen is not recommended for some patients. In this study, we aimed to identify molecular targets sensitive to TAM using a genome-wide gene deletion library screening of fission yeast heterozygous mutants. From the screening, casein kinase 1 gamma 2 (CSNK1G2), a serine-/threonine protein kinase, was the most sensitive target to TAM with a significant cytotoxicity in estrogen receptor-positive (ER+) breast cancer cells but with only a slight toxicity in the case of ER- cells. In addition, tumor sphere formation and expression of breast stem cell marker genes such as CD44/CD2 were greatly inhibited by CSNK1G2 knockdown in ER+ breast cancer cells. Consistently, CSNK1G2 altered ERα activity via phosphorylation, specifically at serine (Ser)167, as well as the regulation of estrogen-responsive element (ERE) of estrogen-responsive genes such as CTSD and GREB1. However, ERα silencing almost completely blocked CSNK1G2-induced TAM sensitivity. In ER+ breast cancer cells, combined treatment with TAM and CSNK1G2 knockdown further enhanced the TAM-mediated decrease in phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (S6K) signaling but not extracellular signal-regulated kinase (ERK) signaling. Inversely, in ER- cells treated with TAM, only ERK and PI3K signaling was altered by CSNK1G2 knockdown. The CK1 inhibitor, D4476, partly mimicked the CSNK1G2 knockdown effect in ER+ breast cancer cells, but with a broader repression ranging from PI3K/AKT/mTOR/S6K to ERK signaling. Collectively, these results suggest that CSNK1G2 plays a key role in sensitizing TAM toxicity in ER+ and ER- breast cancer cells via differently regulating PI3K/AKT/mTOR/S6K and ERK signaling.

Highlights

Breast cancer is one of the most common cancers in women [1]
According to gene ontology (GO) enrichment analysis for biological process, five target genes were associated with the following processes: signal transduction involved in cellular component organization, cytokinesis like septation initiation signaling, and cellular protein metabolic process associated with protein folding (Fig 1C)
These results suggest that the cytotoxic effect of TAM might be potentially attributed to a process that results in the biosynthesis of constituent macromolecules, assembly, arrangement of constituent parts, and/or disassembly of a cellular component in fission yeast S. pombe

Summary

Introduction

Breast cancer is one of the most common cancers in women [1]. The mortality rate of breast cancer dropped, owing to the established system of cancer screening and early comprehensive diagnosis. According to molecular heterogeneity profiling, breast cancer cells can be largely characterized into five intrinsic subtypes: 1) luminal type A expressing high estrogen receptor alpha (ERα) together with progesterone receptor (PR); 2) luminal type B expressing low ERα along with high human epidermal growth factor 2 (HER2); 3) HER2-positive (HER+) possessing luminal characteristics but lack ERα; 4) basal type, called triple-negative meaning ER-/PR-/HER2-; and 5) normal-like expressing high levels of alcohol dehydrogenase 1B (ADH1B), similar to luminal type A [2,3]. Anti-estrogenic agents have been recognized as a reliable and effective treatment to curtail the growth of estrogen-dependent tumors

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