AUTHOR=Cervantes-Badillo Mayte Guadalupe , Paredes-Villa Alejandro , Gómez-Romero Vania , Cervantes-Roldán Rafael , Arias-Romero Luis E. , Villamar-Cruz Olga , González-Montiel Miroslava , Barrios-García Tonatiuh , Cabrera-Quintero Alberto J. , Rodríguez-Gómez Gabriel , Cancino-Villeda Laura , Zentella-Dehesa Alejandro , León-Del-Río Alfonso TITLE=IFI27/ISG12 Downregulates Estrogen Receptor α Transactivation by Facilitating Its Interaction With CRM1/XPO1 in Breast Cancer Cells JOURNAL=Frontiers in Endocrinology VOLUME=11 YEAR=2020 URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2020.568375 DOI=10.3389/fendo.2020.568375 ISSN=1664-2392 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.