The estrogen receptor variants β2 and β5 induce stem cell characteristics and chemotherapy resistance in prostate cancer through activation of hypoxic signaling

// Michelle Faria 1 , Peter Shepherd 2 , Yinghong Pan 1 , Sujash S. Chatterjee 1 , Nora Navone 2 , Jan-Ake Gustafsson 1, 3 and Anders Strom 1 1 University of Houston, Department of Biology and Biochemistry, Center for Nuclear, Receptors and Cell Signaling, Science and Engineering Research Center, Houston, Texas, USA 2 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Huddinge, Sweden Correspondence to: Anders Strom, email: amstrom@uh.edu Keywords: HIF; chemotherapy resistance; HOTAIR; ERbeta2; ERbeta5 Received: September 01, 2018      Accepted: October 31, 2018      Published: November 20, 2018 ABSTRACT Chemotherapy resistant prostate cancer is a major clinical problem. When the prostate cancer has become androgen deprivation resistant, one of the few treatment regimens left is chemotherapy. There is a strong connection between a cancer’s stem cell like characteristics and drug resistance. By performing RNA-seq we observed several factors associated with stem cells being strongly up-regulated by the estrogen receptor β variants, β2 and β5. In addition, most of these factors were also up-regulated by hypoxia. One mechanism of chemotherapy resistance was expression of the hypoxia-regulated, drug transporter genes, where especially ABCG2 and MDR1 were shown to be expressed in recurrent prostate cancer and to cause chemotherapy resistance by efficiently transporting drugs like docetaxel out of the cells. Another mechanism was expression of the hypoxia-regulated Notch3 gene, which causes chemotherapy resistance in urothelial carcinoma, although the mechanism is unknown. It is well known that hypoxic signaling is involved in increasing chemotherapy resistance. Regulation of the hypoxic factors, HIF-1α and HIF-2α is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor β variants, estrogen receptor β2 and β5, bind to and stabilize both HIF-1α and HIF-2α proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor β variants, β2 and β5, could be involved in development of a cancer’s stem cell characteristics and chemotherapy resistance, indicating that targeting these factors could prevent or reverse chemotherapy resistance and cancer stem cell expansion.