Inhibition of Jumonji Histone Demethylases Selectively Suppresses HER2+ Breast Leptomeningeal Carcinomatosis Growth via Inhibition of GMCSF Expression.
Cancer Res
; 81(12): 3200-3214, 2021 06 15.
Article
em En
| MEDLINE
| ID: mdl-33941612
ABSTRACT
HER2+ breast leptomeningeal carcinomatosis (HER2+ LC) occurs when tumor cells spread to cerebrospinal fluid-containing leptomeninges surrounding the brain and spinal cord, a complication with a dire prognosis. HER2+ LC remains incurable, with few treatment options. Currently, much effort is devoted toward development of therapies that target mutations. However, targeting epigenetic or transcriptional states of HER2+ LC tumors might efficiently target HER2+ LC growth via inhibition of oncogenic signaling; this approach remains promising but is less explored. To test this possibility, we established primary HER2+ LC (Lepto) cell lines from nodular HER2+ LC tissues. These lines are phenotypically CD326+CD49f-, confirming that they are derived from HER2+ LC tumors, and express surface CD44+CD24-, a cancer stem cell (CSC) phenotype. Like CSCs, Lepto lines showed greater drug resistance and more aggressive behavior compared with other HER2+ breast cancer lines in vitro and in vivo. Interestingly, the three Lepto lines overexpressed Jumonji domain-containing histone lysine demethylases KDM4A/4C. Treatment with JIB04, a selective inhibitor of Jumonji demethylases, or genetic loss of function of KDM4A/4C induced apoptosis and cell-cycle arrest and reduced Lepto cell viability, tumorsphere formation, regrowth, and invasion in vitro. JIB04 treatment of patient-derived xenograft mouse models in vivo reduced HER2+ LC tumor growth and prolonged animal survival. Mechanistically, KDM4A/4C inhibition downregulated GMCSF expression and prevented GMCSF-dependent Lepto cell proliferation. Collectively, these results establish KDM4A/4C as a viable therapeutic target in HER2+ LC and spotlight the benefits of targeting the tumorigenic transcriptional network. SIGNIFICANCE:
HER2+ LC tumors overexpress KDM4A/4C and are sensitive to the Jumonji demethylase inhibitor JIB04, which reduces the viability of primary HER2+ LC cells and increases survival in mouse models.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Contexto em Saúde:
4_TD
/
6_ODS3_enfermedades_notrasmisibles
Problema de saúde:
4_meningitis
/
6_breast_cancer
Assunto principal:
Neoplasias da Mama
/
Regulação Neoplásica da Expressão Gênica
/
Fator Estimulador de Colônias de Granulócitos e Macrófagos
/
Receptor ErbB-2
/
Carcinomatose Meníngea
/
Histona Desmetilases com o Domínio Jumonji
/
Aminopiridinas
/
Hidrazonas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2021
Tipo de documento:
Article