Title: Hsa-miRNA-765 as a key mediator for inhibiting growth, migration and invasion in fulvestrant-treated prostate cancer.

Authors: Leung, Yuet-Kin; Chan, Queeny Kwan-Yi; Ng, Chi-Fai; Ma, Fanny Man-Ting; Tse, Ho-Man; To, Ka-Fai; Maranchie, Jodi; Ho, Shuk-Mei; Lau, Kin-Mang

Published In PLoS One, (2014)

Abstract: Fulvestrant (ICI-182,780) has recently been shown to effectively suppress prostate cancer cell growth in vitro and in vivo. But it is unclear whether microRNAs play a role in regulating oncogene expression in fulvestrant-treated prostate cancer. Here, this study reports hsa-miR-765 as the first fulvestrant-driven, ERβ-regulated miRNA exhibiting significant tumor suppressor activities like fulvestrant, against prostate cancer cell growth via blockage of cell-cycle progression at the G2/M transition, and cell migration and invasion possibly via reduction of filopodia/intense stress-fiber formation. Fulvestrant was shown to upregulate hsa-miR-765 expression through recruitment of ERβ to the 5'-regulatory-region of hsa-miR-765. HMGA1, an oncogenic protein in prostate cancer, was identified as a downstream target of hsa-miR-765 and fulvestrant in cell-based experiments and a clinical study. Both the antiestrogen and the hsa-miR-765 mimic suppressed HMGA1 protein expression. In a neo-adjuvant study, levels of hsa-miR-765 were increased and HMGA1 expression was almost completely lost in prostate cancer specimens from patients treated with a single dose (250 mg) of fulvestrant 28 days before prostatectomy. These findings reveal a novel fulvestrant signaling cascade involving ERβ-mediated transcriptional upregulation of hsa-miR-765 that suppresses HMGA1 protein expression as part of the mechanism underlying the tumor suppressor action of fulvestrant in prostate cancer.

PubMed ID: 24837491

MeSH Terms: Antineoplastic Agents, Hormonal/pharmacology*; Antineoplastic Agents, Hormonal/therapeutic use; Cell Line, Tumor; Cell Movement*; Cell Proliferation*; Estradiol/analogs & derivatives*; Estradiol/pharmacology; Estradiol/therapeutic use; Estrogen Receptor Antagonists/pharmacology*; Estrogen Receptor Antagonists/therapeutic use; Estrogen Receptor beta/antagonists & inhibitors; Estrogen Receptor beta/metabolism; Fulvestrant; HMGA Proteins/genetics; HMGA Proteins/metabolism; Humans; Male; MicroRNAs/genetics; MicroRNAs/metabolism*; Neoplasm Invasiveness; Prostatic Neoplasms/drug therapy; Prostatic Neoplasms/metabolism*; Prostatic Neoplasms/pathology; Up-Regulation