Abstract
17β-Estradiol (E2) controls diverse physiological processes, including cell proliferation, through its binding to estrogen receptor α (ERα). E2:ERα signaling depends on both the receptor subcellular localization (e.g., nucleus, plasma membrane) and intracellular ERα abundance. Indeed, the control of ERα levels is necessary for the effects of E2, and E2 itself induces ERα degradation and cell proliferation in parallel. Thus, the modulation of intracellular ERα levels is a critical parameter for E2-induced cell proliferation. Therefore, we used this parameter as a bait to identify compounds that influence ERα levels and E2-dependent proliferation in breast cancer (BC) cells from a library of Food and Drug Administration (FDA)-approved drugs. We found that telaprevir (Tel) reduces ERα levels and inhibits BC cell proliferation. Tel is an inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease, but its effect on E2:ERα signaling has not been investigated. Here, for the first time, we analyzed the effects of Tel on intracellular ERα levels and E2:ERα signaling to cell proliferation in different ERα-expressing BC cell lines. Overall, our findings demonstrate that Tel reduces intracellular ERα levels, deregulates E2:ERα signaling and inhibits E2-induced proliferation in BC cells and suggest the potential drug repurposing of Tel for the treatment of BC.
Highlights
The hormone 17β-estradiol (E2), the most effective estrogen, regulates a plethora of physiological effects by binding estrogen receptor α (ERα) [1,2]
To identify new compounds that can influence intracellular ERα levels and E2-dependent proliferation in breast cancer (BC) cells, a screen of Food and Drug Administration (FDA)-approved drugs was performed in our laboratory [14]
The results of the screen suggested that telaprevir (Tel) (Figure 1a) reduces intracellular ERα levels and prevents basal and E2-induced proliferation in MCF-7 cells
Summary
The hormone 17β-estradiol (E2), the most effective estrogen, regulates a plethora of physiological effects by binding estrogen receptor α (ERα) [1,2]. ERα, which belongs to the nuclear receptor superfamily, acts as a ligand-activated transcription factor to drive E2-responsive gene expression through multiple mechanisms (i.e., nuclear and extranuclear signaling) [2,3,4,5,6,7,8,9]. Change in the ERα content is necessary to drive E2-dependent cell functions and regulate cell responsiveness to this hormone. Factors that deregulate the physiological control of intracellular ERα levels can potentially inhibit E2 signaling and downstream effects, such as cell proliferation. The modulation of intracellular ERα levels and E2-dependent BC cell proliferation are interrelated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
