PUBLICATION
The cyclin-like protein, SPY1, regulates the ERα and ERK1/2 pathways promoting tamoxifen resistance
- Authors
- Ferraiuolo, R.M., Tubman, J., Sinha, I., Hamm, C., Porter, L.A.
- ID
- ZDB-PUB-171204-51
- Date
- 2017
- Source
- Oncotarget 8: 23337-23352 (Journal)
- Registered Authors
- Sinha, Indrajit
- Keywords
- Cdk, cell cycle, cyclin, estrogen, tamoxifen
- MeSH Terms
-
- Animals
- Breast Neoplasms/drug therapy*
- Breast Neoplasms/metabolism
- Cell Cycle/physiology
- Cell Cycle Proteins/metabolism*
- Drug Resistance, Neoplasm
- Estrogen Antagonists/pharmacology
- Estrogen Receptor alpha/metabolism*
- Female
- HEK293 Cells
- Humans
- MAP Kinase Signaling System*
- MCF-7 Cells
- Phosphorylation
- Signal Transduction
- Tamoxifen/pharmacology*
- Up-Regulation
- Zebrafish
- PubMed
- 28423577 Full text @ Oncotarget
Citation
Ferraiuolo, R.M., Tubman, J., Sinha, I., Hamm, C., Porter, L.A. (2017) The cyclin-like protein, SPY1, regulates the ERα and ERK1/2 pathways promoting tamoxifen resistance. Oncotarget. 8:23337-23352.
Abstract
The Ras/Raf/MEK/ERK pathway conveys growth factor and mitogen signalling to control the phosphorylation of a plethora of substrates regulating proliferation, survival, and migration. The Ras signalling pathway is frequently associated with poor prognosis and drug resistance in various cancers including those of the blood, breast and prostate. Activation of the downstream effector ERK does not always occur via a linear cascade of events; complicating the targeting of this pathway therapeutically. This work describes a novel positive feedback loop where the cell cycle regulatory factor Spy1 (RINGO; gene SPDYA) activates ERK1/2 in a MEK-independent fashion. Spy1 was originally isolated for the ability to stimulate Xenopus oocyte maturation via a MAPK-signalling pathway and is known to override apoptosis triggered by the DNA damage response. We demonstrate that mammalian Spy1-mediated ERK activation increases ligand-independent phosphorylation and activation of estrogen receptor α, correlating with a decrease in tamoxifen sensitivity. This could define a novel druggable mechanism driving proliferation and resistance in select cancers.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping