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ONECUT2 is a druggable driver of luminal to basal breast cancer plasticity.
Zamora, Irene; Gutiérrez, Mirian; Pascual, Alex; Pajares, María J; Barajas, Miguel; Perez, Lillian M; You, Sungyong; Knudsen, Beatrice S; Freeman, Michael R; Encío, Ignacio J; Rotinen, Mirja.
Afiliación
  • Zamora I; Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
  • Gutiérrez M; Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
  • Pascual A; Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
  • Pajares MJ; Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
  • Barajas M; IdiSNA, Navarre Institute for Health Research, Pamplona, Navarre, Spain.
  • Perez LM; Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
  • You S; IdiSNA, Navarre Institute for Health Research, Pamplona, Navarre, Spain.
  • Knudsen BS; Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Freeman MR; Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • Encío IJ; Department of Pathology, University of Utah, Salt Lake City, UT, USA.
  • Rotinen M; Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Cell Oncol (Dordr) ; 2024 May 31.
Article en En | MEDLINE | ID: mdl-38819630
ABSTRACT

PURPOSE:

Tumor heterogeneity complicates patient treatment and can be due to transitioning of cancer cells across phenotypic cell states. This process is associated with the acquisition of independence from an oncogenic driver, such as the estrogen receptor (ER) in breast cancer (BC), resulting in tumor progression, therapeutic failure and metastatic spread. The transcription factor ONECUT2 (OC2) has been shown to be a master regulator protein of metastatic castration-resistant prostate cancer (mCRPC) tumors that promotes lineage plasticity to a drug-resistant neuroendocrine (NEPC) phenotype. Here, we investigate the role of OC2 in the dynamic conversion between different molecular subtypes in BC.

METHODS:

We analyze OC2 expression and clinical significance in BC using public databases and immunohistochemical staining. In vitro, we perform RNA-Seq, RT-qPCR and western-blot after OC2 enforced expression. We also assess cellular effects of OC2 silencing and inhibition with a drug-like small molecule in vitro and in vivo.

RESULTS:

OC2 is highly expressed in a substantial subset of hormone receptor negative human BC tumors and tamoxifen-resistant models, and is associated with poor clinical outcome, lymph node metastasis and heightened clinical stage. OC2 inhibits ER expression and activity, suppresses a gene expression program associated with luminal differentiation and activates a basal-like state at the gene expression level. We also show that OC2 is required for cell growth and survival in metastatic BC models and that it can be targeted with a small molecule inhibitor providing a novel therapeutic strategy for patients with OC2 active tumors.

CONCLUSIONS:

The transcription factor OC2 is a driver of BC heterogeneity and a potential drug target in distinct cell states within the breast tumors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Oncol (Dordr) Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Países Bajos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cell Oncol (Dordr) Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Países Bajos