Related Experiment Video

Updated: May 14, 2026

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
19:44

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen

Published on: May 30, 2012

Regulation of tamoxifen sensitivity by a PAK1-EBP1 signalling pathway in breast cancer

A Ghosh1, S Awasthi, J R Peterson

  • 1Greenebaum Cancer Center, University of Maryland School of Medicine, BRB 9-029, 655 W. Baltimore Street, Baltimore, MD 21201, USA.

British Journal of Cancer
|January 31, 2013
PubMed
Abstract

Insights

Inhibition of PAK1 kinase activity can overcome tamoxifen resistance in breast cancer by preventing EBP1 phosphorylation. This strategy may restore EBP1 function and sensitivity to hormone therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • ErbB3-binding protein 1 (EBP1) sensitizes breast cancer to tamoxifen by reducing ErbB2 levels.
  • p21-activated kinase 1 (PAK1) phosphorylates EBP1 at T261, inducing tamoxifen resistance.
  • Overexpression of ErbB2 is linked to tamoxifen resistance in breast cancer.

Purpose of the Study:

  • To investigate if inhibiting PAK1 activity could restore EBP1 function and overcome tamoxifen resistance in ErbB2-overexpressing breast cancer cells.
  • To determine the role of EBP1 phosphorylation at T261 in tamoxifen resistance.

Main Methods:

  • Western blotting to assess EBP1 and ErbB2 protein levels.
  • Cell viability assays to measure tamoxifen sensitivity.
  • Transient transfection with EBP1 mutants (T261E, T261A) and shRNA-mediated EBP1 ablation.
  • Pharmacological inhibition of PAK1 using IPA-3.

Main Results:

  • EBP1 T261E mutant mimicked PAK1 phosphorylation, increasing ErbB2 levels.
  • EBP1 T261A mutant reversed PAK1-induced tamoxifen resistance.
  • Pharmacological inhibition of PAK1 with IPA-3 sensitized cells to tamoxifen when EBP1 was overexpressed.
  • IPA-3 treatment decreased ErbB2 levels in EBP1-overexpressing cells, correlating with increased tamoxifen sensitivity.

Conclusions:

  • EBP1 phosphorylation by PAK1 is a mechanism contributing to tamoxifen resistance in breast cancer.
  • PAK1 inhibitors, like IPA-3, may be effective therapeutic agents for breast cancer patients with high EBP1 expression.
  • Targeting PAK1 could be a viable strategy to re-sensitize hormone-refractory breast cancer to tamoxifen.

More Related Videos

Exploring the Pharmacological Action and Molecular Mechanism of Salidroside in Inhibiting MCF-7 Cell Proliferation and Migration11:13

Exploring the Pharmacological Action and Molecular Mechanism of Salidroside in Inhibiting MCF-7 Cell Proliferation and Migration

Published on: June 9, 2023

Related Concept Videos

Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...