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Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells
16:24

Profiling of Estrogen-regulated MicroRNAs in Breast Cancer Cells

Published on: February 21, 2014

AKT regulation of estrogen receptor beta transcriptional activity in breast cancer

Bich N Duong1, Steven Elliott, Daniel E Frigo

  • 1Center for Bioenvironmental Research, Tulane University, New Orleans, LA, USA.

Cancer Research
|September 5, 2006
PubMed

Insights

The AKT pathway enhances estrogen receptor beta (ER beta) activity, particularly its activation function-2 domain, by interacting with coactivators like GRIP1. This cross-talk may impact breast cancer endocrine therapy response.

Area of Science:

  • Molecular and Cellular Biology
  • Endocrinology
  • Oncology

Background:

  • Growth factor signaling via the PI3K-AKT pathway influences estrogen receptor alpha (ER alpha) activity and tamoxifen resistance in breast cancer.
  • The role of the PI3K-AKT pathway in regulating the transcriptional activity of estrogen receptor beta (ER beta) remains largely unexplored.

Purpose of the Study:

  • To investigate the regulation of ER beta transcriptional activity by the PI3K-AKT signaling pathway.
  • To elucidate the specific domains and coactivators involved in AKT-mediated ER beta regulation.

Main Methods:

  • Analysis of breast cancer tissue arrays to correlate AKT and ER beta expression.
  • Reporter gene assays with pharmacologic and molecular AKT inhibitors and activators.
  • Mammalian two-hybrid and one-hybrid assays to assess protein-protein interactions and domain activity.
  • In vitro kinase assays to determine direct phosphorylation events.

Main Results:

  • A positive association between AKT and ER beta expression was observed in clinical breast cancer specimens.
  • AKT was found to potentiate ER beta transcriptional activity, primarily through the activation function-2 (AF2) domain, requiring residue K269.
  • AKT enhanced the recruitment of coactivators steroid receptor coactivator 1 (SRC1) and glucocorticoid receptor-interacting protein 1 (GRIP1) to ER beta.
  • AKT directly phosphorylated GRIP1, and AKT and GRIP1 cooperatively increased ER beta-mediated transcription.

Conclusions:

  • The PI3K-AKT pathway directly regulates ER beta transcriptional activity, involving its AF2 domain and coactivators like GRIP1.
  • AKT's phosphorylation of GRIP1 and enhanced coactivator recruitment highlight a significant cross-talk between PI3K-AKT and ER beta signaling.
  • This intricate cross-talk may represent a critical factor influencing breast cancer progression and response to endocrine therapies.

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