Abstract
The estrogen receptor alpha (ERα) is a ligand-activated transcription factor whose activity is modulated by its interaction with multiple protein complexes. In this work, we have identified the protein interferon alpha inducible protein 27 (IFI27/ISG12) as a novel ERα-associated protein. IFI27/ISG12 transcription is regulated by interferon and estradiol and its overexpression is associated to reduced overall survival in ER+ breast cancer patients but its function in mammary gland tissue remains elusive. In this study we showed that overexpression of IFI27/ISG12 in breast cancer cells attenuates ERα transactivation activity and the expression of ERα-dependent genes. Our results demonstrated that IFI27/ISG12 overexpression in MCF-7 cells reduced their proliferation rate in 2-D and 3-D cell culture assays and impaired their ability to migrate in a wound-healing assay. We show that IFI27/ISG12 downregulation of ERα transactivation activity is mediated by its ability to facilitate the interaction between ERα and CRM1/XPO1 that mediates the nuclear export of large macromolecules to the cytoplasm. IFI27/ISG12 overexpression was shown to impair the estradiol-dependent proliferation and tamoxifen-induced apoptosis in breast cancer cells. Our results suggest that IFI27/ISG12 may be an important factor in regulating ERα activity in breast cancer cells by modifying its nuclear versus cytoplasmic protein levels. We propose that IFI27/ISG12 may be a potential target of future strategies to control the growth and proliferation of ERα−positive breast cancer tumors.
Highlights
The estrogen receptor a (ERa) is a ligand-activated transcription factor that mediates the effects of the hormone estrogen (17bestradiol; E2) on cell proliferation and differentiation in mammary gland and participates in maintenance of skeletal system, metabolic homeostasis and in development of central nervous system [1]
Physical interaction between endogenous estrogen receptor alpha (ERa) and ISG12 proteins was determined in human breast cancer cell lines MCF-7, T47D, and ZR-75-1 using the corresponding two primary antibodies raised in different species
10% of the protein extracts used in each immunoprecipitation assay were analyzed by Western blot using anti- CRM1/XPO1or anti-ERa to confirm the presence of the proteins (Figure 4B, Input). These results indicate that ISG12 promotes the interaction of ERa with the nuclear exportin CRM1/XPO1 and suggest that the ISG12-dependent down-regulation of ERa transactivation may be mediated by its export from the nucleus in breast cancer cells
Summary
The estrogen receptor a (ERa) is a ligand-activated transcription factor that mediates the effects of the hormone estrogen (17bestradiol; E2) on cell proliferation and differentiation in mammary gland and participates in maintenance of skeletal system, metabolic homeostasis and in development of central nervous system [1]. The functional synergistic interaction between the unique transcriptional properties of AF1 and AF2 domains is responsible for the full ligand-dependent ERa transactivation. The binding of E2 to ERa produces a major structural rearrangement on its ligand binding domain that allows AF2 to interact with a large array of coactivator proteins that include SRC-1, SRC-2/GRIP1/TIF2/NCoA2, SRC3/RAC3/p/CIP/ACTR/AIB1, CREB-binding protein (CBP)/p300, and CBP-associated factor (P/CAF) that increase ERa transcriptional activity by relaxing the chromatin structure through their histone acetyl-transferase activity [9,10,11]. The exchange of coactivators and corepressors is a mechanism that finetunes the ERa transactivation activity in hormone responsive tissues and allows this transcription factor to oscillate between its functions as activator and repressor of gene expression [24, 25]
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