The Estrogen Receptor variants ß2 and ß5 Induce Stem Cell Characteristics and Chemotherapy Resistance in Prostate Cancer through activation of Hypoxic Signaling

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 ß variants, ß2 and ß5. 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-1a and HIF-2a is very complex and extends far beyond hypoxia itself. We have recently shown that two of the estrogen receptor ß variants, estrogen receptor ß2 and ß5, bind to and stabilize both HIF-1a and HIF-2a proteins leading to expression of HIF target genes. This study suggests that increased expression of the estrogen receptor ß variants, ß2 and ß5, 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. Overall design: Examination of the transcriptome changed by two estrogen reseptor beta variants (ERbeta2 and ERbeta5). Control (lacking expression) and variant expressing cells in two repeats

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Faria M, Shepherd P, Pan Y, Chatterjee SS, Navone N, Gustafsson JÅ, Strom A