title: Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer.
abstract: Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation of developmental genes. For the homeobox gene HOXC10, methylation occurred in a CpG shore, which overlapped with a functional ER binding site, causing repression of HOXC10 expression. Although short-term blockade of ER signaling caused relief of HOXC10 repression in both cell lines and breast tumors, it also resulted in concurrent recruitment of EZH2 and increased H3K27me3, ultimately transitioning to increased DNA methylation and silencing of HOXC10. Reduced HOXC10 in vitro and in xenografts resulted in decreased apoptosis and caused antiestrogen resistance. Supporting this, we used paired primary and metastatic breast cancer specimens to show that HOXC10 was reduced in tumors that recurred during AI treatment. We propose a model in which estrogen represses apoptotic and growth-inhibitory genes such as HOXC10, contributing to tumor survival, whereas AIs induce these genes to cause apoptosis and therapeutic benefit, but long-term AI treatment results in permanent repression of these genes via methylation and confers resistance. Therapies aimed at inhibiting AI-induced histone and DNA methylation may be beneficial in blocking or delaying AI resistance.
authors.affiliation: Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Thushangi N
authors.initials: TN
authors.lastname: Pathiraja
authors.forename: Shweta R
authors.initials: SR
authors.lastname: Nayak
authors.forename: Yuanxin
authors.initials: Y
authors.lastname: Xi
authors.forename: Shiming
authors.initials: S
authors.lastname: Jiang
authors.forename: Jason P
authors.initials: JP
authors.lastname: Garee
authors.forename: Dean P
authors.initials: DP
authors.lastname: Edwards
authors.forename: Adrian V
authors.initials: AV
authors.lastname: Lee
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Shea
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Santen
authors.forename: Frank
authors.initials: F
authors.lastname: Gannon
authors.forename: Sara
authors.initials: S
authors.lastname: Kangaspeska
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Richer
authors.forename: Anthony
authors.initials: A
authors.lastname: Elias
authors.forename: Marie
authors.initials: M
authors.lastname: McIlroy
authors.forename: Leonie S
authors.initials: LS
authors.lastname: Young
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.forename: Rachel
authors.initials: R
authors.lastname: Schiff
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D065150:Cellular Reprogramming / Q000187:drug effects / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D047072:Aromatase Inhibitors; D004967:Estrogens; C410304:HOXC10 protein, human; D006657:Histones; D018398:Homeodomain Proteins