KDM4 Inhibition Targets Breast Cancer Stem–like Cells

Autor: Anita Allen, Marie Follo, Sylvia Urban, Roland Schüle, Jochen Maurer, Stella S. Stepputtis, Melanie Boerries, Jeffrey A. Stafford, Dominica Willmann, Peter Bronsert, Fides Zenk, Toufike Kanouni, Juliane Strietz, Michael Brennan Wallace, Nicola Iovino, Jiangchun Xu, Eric Metzger, Amelie Proske, Bogdan-Tiberius Preca, Elmar Stickeler
Rok vydání: 2017
Předmět:
0301 basic medicine
CA15-3
Oncology
Jumonji Domain-Containing Histone Demethylases
Cancer Research
medicine.medical_specialty
medicine.medical_treatment
Triple Negative Breast Neoplasms
Mice
SCID
Heterocyclic Compounds
4 or More Rings
03 medical and health sciences
0302 clinical medicine
Breast cancer
Mice
Inbred NOD
RNA interference
Internal medicine
Tumor Cells
Cultured
medicine
Animals
Humans
Epigenetics
Enzyme Inhibitors
Cell Proliferation
Regulation of gene expression
Chemotherapy
Molecular Structure
biology
business.industry
Gene Expression Profiling
Cancer
medicine.disease
Xenograft Model Antitumor Assays
ErbB Receptors
Gene Expression Regulation
Neoplastic
030104 developmental biology
030220 oncology & carcinogenesis
Neoplastic Stem Cells
biology.protein
Demethylase
Female
RNA Interference
business
Zdroj: Cancer research : an official organ of the American Association for Cancer Research
ISSN: 1538-7445
0008-5472
DOI: 10.1158/0008-5472.can-17-1754
Popis: Traditional treatments for breast cancer fail to address therapy-resistant cancer stem–like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast cancer stem–like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast cancer. Cancer Res; 77(21); 5900–12. ©2017 AACR.
Databáze: OpenAIRE
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