title: Histone demethylase JMJD2B functions as a co-factor of estrogen receptor in breast cancer proliferation and mammary gland development.
abstract: Estrogen is a key regulator of normal function of female reproductive system and plays a pivotal role in the development and progression of breast cancer. Here, we demonstrate that JMJD2B (also known as KDM4B) constitutes a key component of the estrogen signaling pathway. JMJD2B is expressed in a high proportion of human breast tumors, and that expression levels significantly correlate with estrogen receptor (ER) positivity. In addition, 17-beta-estradiol (E2) induces JMJD2B expression in an ERα dependent manner. JMJD2B interacts with ERα and components of the SWI/SNF-B chromatin remodeling complex. JMJD2B is recruited to ERα target sites, demethylates H3K9me3 and facilitates transcription of ER responsive genes including MYB, MYC and CCND1. As a consequence, knockdown of JMJD2B severely impairs estrogen-induced cell proliferation and the tumor formation capacity of breast cancer cells. Furthermore, Jmjd2b-deletion in mammary epithelial cells exhibits delayed mammary gland development in female mice. Taken together, these findings suggest an essential role for JMJD2B in the estrogen signaling, and identify JMJD2B as a potential therapeutic target in breast cancer.
authors: The Campbell Family Cancer Research Institute, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada. mkawz-tky@umin.ac.jp
authors: Masahito
authors: M
authors: Kawazu
authors: Kayoko
authors: K
authors: Saso
authors: Kit I
authors: KI
authors: Tong
authors: Tracy
authors: T
authors: McQuire
authors: Kouichiro
authors: K
authors: Goto
authors: Dong-Ok
authors: DO
authors: Son
authors: Andrew
authors: A
authors: Wakeham
authors: Makoto
authors: M
authors: Miyagishi
authors: Tak W
authors: TW
authors: Mak
authors: Hitoshi
authors: H
authors: Okada
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D018390:Gene Targeting; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000254:growth & development*; D051379:Mice; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
chemical_list: D047628:Estrogen Receptor alpha; D056484:Jumonji Domain-Containing Histone Demethylases; C523637:KDM4B protein, human