Oncotarget

Research Papers:

The cyclin-like protein, SPY1, regulates the ERα and ERK1/2 pathways promoting tamoxifen resistance

Rosa-Maria Ferraiuolo, Janice Tubman, Indrajit Sinha, Caroline Hamm and Lisa Ann Porter _

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Oncotarget. 2017; 8:23337-23352. https://doi.org/10.18632/oncotarget.15578

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Abstract

Rosa-Maria Ferraiuolo1, Janice Tubman1,3, Indrajit Sinha3, Caroline Hamm1,2, Lisa Ann Porter1

1Department of Biological Sciences, University of Windsor, Windsor, ON N9B 3P4, Canada

2Windsor Regional Hospital, Windsor, ON N8W 1L9, Canada

3Acenzia Inc, Tecumseh, ON N9A 6J3, Canada

Correspondence to:

Lisa Ann Porter, email: lporter@uwindsor.ca

Keywords: Cdk, cyclin, cell cycle, estrogen, tamoxifen

Received: February 15, 2016     Accepted: February 12, 2017     Published: February 21, 2017

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.


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