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Updated: Feb 13, 2026

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
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Timeless Is a Novel Estrogen Receptor Co-activator Involved in Multiple Signaling Pathways in MCF-7 Cells

Chantal Beatrice Magne Nde1, Gloria Casas Gimeno1, Maria Docanto2

  • 1Cancer Drugs Discovery, Centre of Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia.

Journal of Molecular Biology
|March 21, 2018
PubMed

Insights

Timeless protein acts as an estrogen receptor alpha (ERα) coactivator, enhancing ERα-driven gene regulation and tumor growth. This discovery links Timeless to steroid hormone function and tamoxifen resistance mechanisms.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Cancer Research

Background:

  • Estrogen receptor alpha (ERα) activation drives cell division and tumor growth by regulating target genes.
  • Specific protein recruitment in ERα activation is not fully understood.
  • Timeless, a circadian rhythm gene homolog, predicts tamoxifen relapse and affects genomic stability.

Purpose of the Study:

  • To investigate the interaction between Timeless and ERα.
  • To determine if Timeless functions as an ERα coactivator.
  • To elucidate the mechanism linking Timeless to ERα activity and tamoxifen resistance.

Main Methods:

  • Assessed Timeless-ERα binding and transcriptional enhancement.
  • Examined the role of the Timeless LXXLL motif and ERα PARylation.
  • Investigated recruitment of Timeless and ERα to target gene promoters (GREB1, cMyc).

Main Results:

  • Human Timeless acts as an ERα coactivator, binding to ERα and boosting its transcriptional activity.
  • Timeless overexpression increases PARP1 expression and enhances ERα-mediated gene regulation.
  • Timeless and ERα are co-recruited to the GREB1 and cMyc promoters, mediated by the Timeless LXXLL motif and ERα PARylation.

Conclusions:

  • Timeless is a novel ERα coactivator, linking circadian rhythm genes to steroid hormone signaling.
  • The findings provide a mechanistic basis for Timeless's association with tamoxifen resistance.
  • Timeless is identified as a key regulator of ERα transactivation.
Keywords:
breast cancercoactivatorestrogen receptortamoxifen

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