LSD1 (also known as KDM1A) is a histone demethylase that has been shown to play both oncogenic and tumor suppressor roles in breast cancer. However, the exact context under which it functions as a tumor suppressor or oncoprotein remains largely elusive. To address this, we characterized its role in normal mammary epithelial cells (MECs) and found MEC-specific ablation of Lsd1 largely phenocopied that of Gata3, which encodes a master regulatory transcription factor for luminal MECs. In the luminal lineage, LSD1-loss led to reduction in both mature ductal and alveolar luminal subpopulations. In human luminal breast cancer cells, we found LSD1 interacts with GATA3 and their common target genes are highly related to breast cancer. In particular, we found LSD1 might be recruited by GATA3 to the GATA3 promoter region, to positively regulate GATA3 expression via demethylation of H3K9me2. Knockdown of LSD1 led to increased invasion of luminal breast cancer cells, in part via downregulation of GATA3 and multiple cell junction genes (e.g., CDH1, VCL, CTNNA1), as well as upregulation of mammary stem/progenitor cell genes (e.g., ELF5, ITGB1). However, LSD1 knockdown also led to reduced proliferation of luminal breast cancer cells, in part via downregulation of RBBP4 (encoding a Histone-binding protein) and upregulation of CDKN1A (encoding p21). Collectively, our data suggest that LSD1 is required for maintaining luminal MEC differentiation and survival and for suppressing luminal breast cancer cell invasion, in part via GATA3. As inhibitors of LSD1 are currently under clinical trials (e.g., in leukemia), our data suggest that although treatment of luminal breast cancer by the LSD1 inhibitor may lead to reduced tumor cell proliferation (and thus tumor shrinkage), the treatment may also lead to increased invasion of surviving breast cancer cells. Thus, our study is expected to have important implications for developing better epigenetic therapy in an individualized, context-dependent fashion.

Citation Format: Xin Hu, Dongxi Xiang, Luwei Tao, Ying Xie, Yue Jin, Yidi Guo, Luca Pinello, Guo-Cheng Yuan, Zhe Li. LSD1 maintains differentiation and survival of mammary luminal cells and suppresses invasion of luminal breast cancer cells via GATA3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2563. doi:10.1158/1538-7445.AM2017-2563