The ERβ4 variant induces transformation of the normal breast mammary epithelial cell line MCF-10A; the ERβ variants ERβ2 and ERβ5 increase aggressiveness of TNBC by regulation of hypoxic signaling

// Michelle Faria 1 , Samaneh Karami 1 , Sergio Granados-Principal 2 , Prasenjit Dey 3, 4 , Akanksha Verma 5 , Dong S. Choi 6 , Olivier Elemento 5 , Tasneem Bawa-Khalfe 1 , Jenny C. Chang 6 , Anders M. Strom 1 and Jan-Åke Gustafsson 1, 7 1 University of Houston, Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, Science & Engineering Research Center, Houston, Texas, USA 2 Department of Medical Oncology, Hospital of Jaen, Jaen, Spain 3 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Institute for Computational Biomedicine, Department of Physiology and Biophysics Weill Cornell Medicine, New York, NY, USA 6 Methodist Cancer Center, Houston Methodist Hospital, Houston, Texas, USA 7 Department of BioSciences and Nutrition, Karolinska Institutet, Huddinge, Sweden Correspondence to: Anders M. Strom, email: amstrom@uh.edu Keywords: slug; twist1; SOX2; CD133; c-Myc Received: July 22, 2017 Accepted: November 05, 2017 Published: January 10, 2018 ABSTRACT Triple negative breast cancer (TNBC) still remains a challenge to treat in the clinic due to a lack of good targets for treatment. Although TNBC lacks expression of ERα, the expression of ERβ and its variants are detected quite frequently in this cancer type and can represent an avenue for treatment. We show that two of the variants of ERβ, namely ERβ2 and ERβ5, control aggressiveness of TNBC by regulating hypoxic signaling through stabilization of HIF-1α. RNA-seq of patient derived xenografts (PDX) from TNBC shows expression of ERβ2, ERβ4 and ERβ5 variants in more than half of the samples. Furthermore, expression of ERβ4 in the immortalized, normal mammary epithelial cell line MCF-10A that is resistant to tumorsphere formation caused transformation and development of tumorspheres. By contrast, ERβ1, ERβ2 or ERβ5 were unable to support tumorsphere formation. We have previously shown that all variants except ERβ1 stabilize HIF-1α but only ERβ4 appears to have the ability to transform normal mammary epithelial cells, pointing towards a unique property of ERβ4. We propose that ERβ variants may be good diagnostic tools and also serve as novel targets for treatment of breast cancer.