The cyclin-like protein, SPY1, regulates the ERα and ERK1/2 pathways promoting tamoxifen resistance
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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
Lisa Ann Porter, email: [email protected]
Keywords: Cdk, cyclin, cell cycle, estrogen, tamoxifen
Received: February 15, 2016 Accepted: February 12, 2017 Published: February 21, 2017
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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