The histone lysine demethylase KDM4 subfamily, comprised of four members (A, B, C, and D), play critical roles in controlling transcription, chromatin architecture and cellular differentiation. Although KDM4 family members have a high degree of homology, they may play different roles in various types of breast cancer. The goal of this study is to analyze the genomic and transcriptomic alterations of the KDM4 subfamily in different subtypes of breast cancer, and explore the therapeutic potential of a novel KDM4 inhibitor in aggressive basal breast cancer.

We conducted a large-scale meta-analysis of KDM4A, B, C, and D in breast cancer and identified associations among recurrent copy number alterations, gene expression and breast cancer subtypes. We examined KDM4 expression in a panel of non-tumorigenic and cancerous breast epithelial cell lines using quantitative RT-PCR and Western blot assays, and assessed global histone 3 methylation levels by Western blot in a panel of breast cancer cell lines. Next, we tested a novel inhibitor of the KDM4 demethylases, small molecule NCDM-32B, for its ability to attenuate basal breast cancer cell growth and impair metastatic potential. Finally, to examine gene expression changes induced by NCDM-32B, we conducted expression profiling and pathway analyses.

We found that the KDM4 members show different expression patterns in subtypes of breast cancer. Our findings suggest that H3 global methylation levels vary among different breast cancer cell lines. We demonstrated that NCDM-32B significantly impaired viability, cellular growth and transforming phenotypes of basal breast cancer in vitro. Furthermore, NCDM-32B impaired several critical pathways and classical oncogenes, including MET, CDC26, and CDK6, that drive cellular proliferation and transformation in breast cancer.

In summary, our findings add layers of information to the genomic and transcriptomic profiles of the KDM4 subfamily in different subtypes of breast cancer. We provide the first evidence that a novel KDM4 demethylase inhibitor, the small molecule NCDM-32B, led to significant inhibition of cellular growth of basal breast cancer in vitro. These findings lay the foundation for evaluating KDM4 inhibitors as therapeutic approaches against aggressive breast cancer.

Citation Format: Andreana N. Holowatyj, Qin Ye, Jack Wu, Hui Liu, Lihong Zhang, Takayoshi Suzuki, Zeng-Quan Yang. Genetic alterations of KDM4 subfamily and therapeutic effect of novel demethylase inhibitor in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 98. doi:10.1158/1538-7445.AM2015-98