Abstract
Cyclin E2 gene amplification, but not cyclin E1, has been recently defined as marker for poor prognosis in breast cancer, and appears to play a major role in proliferation and therapeutic resistance in several breast cancer cells. Our laboratory has previously reported that stimulation of the hERG1 potassium channel with selective activators led to down-regulation of cyclin E2 in breast cancer cells. In this work, we demonstrate that stimulation of hERG1 promotes an ubiquitin-proteasome-dependent degradation of cyclin E2 in multiple breast cancer cell lines representing Luminal A, HER2+ and Trastuzumab-resistant breast cancer cells. In addition we have also reveal that hERG1 stimulation induces an increase in intracellular calcium that is required for cyclin E2 degradation. This novel function for hERG1 activity was specific for cyclin E2, as cyclins A, B, D E1 were unaltered by the treatment. Our results reveal a novel mechanism by which hERG1 activation impacts the tumor marker cyclin E2 that is independent of cyclin E1, and suggest a potential therapeutic use for hERG1 channel activators.
Highlights
Type-E cyclins are encoded by two distinct genes (CCNE1 and CCNE2) that play a major role in promoting transition from G0/G1 to S phase of the cell cycle [1,2,3]
Reported to be undetectable in non-transformed cells [7], overexpression of cyclin E2 in breast cancer cells has been found to be associated with increased resistance to both chemotherapy and endocrine therapy [8, 9], and cyclin E2 has been included in the gene expression pattern that predict poor prognosis in endocrine-resistant and metastatic breast cancers
In the present work we have investigated on the mechanism through which stimulation of hERG1 channel leads to a rapid down-regulation of cyclin E2, assessed the impact of this inhibition in tumor cells arising from a variety of breast cancer subtypes, and considered the potential of hERG1 activators in treating breast cancers that have become resistant to therapy
Summary
Type-E cyclins are encoded by two distinct genes (CCNE1 and CCNE2) that play a major role in promoting transition from G0/G1 to S phase of the cell cycle [1,2,3]. Both E cyclins have been associated with mechanisms of tumor progression, only the CCNE2 gene has been reported to be preferentially amplified in different types of breast tumors [4,5,6]. During the S phase of the cell cycle, GSK-3β-dependent phosphorylation of cyclin E1 plays a major role in promoting recognition and ubiquitination of cyclin E1 by the ubiquitin ligase Fbw. The mechanisms that control cyclin E2 turnover are less well established
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