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CSNK1G2 differently sensitizes tamoxifen-induced decrease in PI3K/AKT/mTOR/S6K and ERK signaling according to the

Anh Thu Nguyen Hoang1, Kwang-Lae Hoe2, Sook-Jeong Lee1

  • 1Department of Bioactive Material Sciences, Jeonbuk National University, Jeonju, Jeollabuk-do, Republic of Korea.

Plos One
|April 16, 2021
PubMed

Insights

Casein kinase 1 gamma 2 (CSNK1G2) is identified as a key target that sensitizes breast cancer cells to tamoxifen (TAM) treatment, particularly in estrogen receptor-positive cells. This finding offers new insights for improving tamoxifen therapy efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Tamoxifen (TAM) is a widely used selective estrogen receptor modulator for breast cancer treatment.
  • Prolonged tamoxifen use presents challenges, necessitating the identification of novel therapeutic targets and strategies.
  • Understanding molecular mechanisms underlying tamoxifen sensitivity is crucial for optimizing treatment outcomes.

Purpose of the Study:

  • To identify molecular targets that modulate tamoxifen sensitivity using a genome-wide screen in fission yeast.
  • To investigate the role of casein kinase 1 gamma 2 (CSNK1G2) in tamoxifen-induced cytotoxicity and breast cancer progression.
  • To elucidate the signaling pathways regulated by CSNK1G2 in response to tamoxifen in different breast cancer subtypes.

Main Methods:

  • Genome-wide gene deletion library screening in fission yeast to identify tamoxifen-sensitive targets.
  • CSNK1G2 knockdown experiments in estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancer cells.
  • Analysis of tumor sphere formation, stem cell marker gene expression, and estrogen receptor alpha (ERα) activity.
  • Western blot analysis to assess key signaling pathways including PI3K/AKT/mTOR/S6K and ERK.

Main Results:

  • CSNK1G2 was identified as a highly sensitive target, exhibiting significant cytotoxicity in ER+ breast cancer cells upon tamoxifen treatment.
  • CSNK1G2 knockdown inhibited tumor sphere formation and breast stem cell marker expression in ER+ cells.
  • CSNK1G2 modulated ERα activity via phosphorylation at Ser167, influencing estrogen-responsive genes and tamoxifen sensitivity.
  • Combined tamoxifen treatment and CSNK1G2 knockdown enhanced the inhibition of PI3K/AKT/mTOR/S6K signaling in ER+ cells, while affecting ERK and PI3K signaling in ER- cells.

Conclusions:

  • CSNK1G2 plays a critical role in sensitizing both ER+ and ER- breast cancer cells to tamoxifen toxicity.
  • CSNK1G2 differentially regulates PI3K/AKT/mTOR/S6K and ERK signaling pathways, contributing to tamoxifen response.
  • Targeting CSNK1G2 represents a potential therapeutic strategy to enhance tamoxifen efficacy in breast cancer treatment.

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