DAXX Suppresses Tumor-Initiating Cells in Estrogen Receptor-Positive Breast Cancer Following Endocrine Therapy

Cancer Research
Daniel S PeifferClodia Osipo

Abstract

Estrogen receptor (ER)-positive breast cancer recurrence is thought to be driven by tumor-initiating cells (TIC). TICs are enriched by endocrine therapy through NOTCH signaling. Side effects have limited clinical trial testing of NOTCH-targeted therapies. Death-associated factor 6 (DAXX) is a newly identified marker whose RNA expression inversely correlates with NOTCH in human ER+ breast tumor samples. In this study, knockdown and overexpression approaches were used to investigate the role of DAXX on stem/pluripotent gene expression, TIC survival in vitro, and TIC frequency in vivo, and the mechanism by which DAXX suppresses TICs in ER+ breast cancer. 17β-Estradiol (E2)-mediated ER activation stabilized the DAXX protein, which was required for repressing stem/pluripotent genes (NOTCH4, SOX2, OCT4, NANOG, and ALDH1A1), and TICs in vitro and in vivo. Conversely, endocrine therapy promoted rapid protein depletion due to increased proteasome activity. DAXX was enriched at promoters of stem/pluripotent genes, which was lost with endocrine therapy. Ectopic expression of DAXX decreased stem/pluripotent gene transcripts to levels similar to E2 treatment. DAXX-mediated repression of stem/pluripotent genes and suppression of TICs was dep...Continue Reading

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Citations

Mar 27, 2020·Medical Sciences : Open Access Journal·Ugo TestaElvira Pelosi
Oct 3, 2020·Cells·McKenna BeLow, Clodia Osipo
May 25, 2020·Journal of Cancer Research and Clinical Oncology·Hai-Zhen ZhuZheng-Tang Chen
Aug 29, 2020·Journal of the Egyptian National Cancer Institute·Marwa T HussienAbeer Ibrahim
Mar 24, 2020·British Journal of Cancer·Chaofan WuJin Zhou
Jan 8, 2021·Journal of the American Heart Association·Joshua A UhlornHeddwen L Brooks
Mar 20, 2021·Seminars in Cancer Biology·Rui ZhangSuling Liu

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