Abstract
LSD1, an epigenetic modifier, and PELP1, an estrogen receptor co-activator, integrate estrogen receptor ERα and HER2 receptor tyrosine kinase signaling to promote aromatase expression and hormone resistance in a preclinical model of post-menopausal breast cancer. In the previous issue of Breast Cancer Research, Cortez et al. show, for the first time, that knockdown or drug-mediated inhibition of PELP1 or LSD1 suppresses LSD1-mediated transcriptionally activating histone marks at ERα target genes, inhibits aromatase gene expression, and sensitizes hormone refractory breast cancer cells to tamoxifen or letrozole treatments. The relevance of PELP1-LSD1 signaling to other nuclear hormone receptor-dependent cancers and structural considerations for the selective drug targeting of LSD1 are further discussed in this editorial.
Highlights
LSD1, an epigenetic modifier, and PELP1, an estrogen receptor co-activator, integrate estrogen receptor estrogen receptor-alpha (ERα) and HER2 receptor tyrosine kinase signaling to promote aromatase expression and hormone resistance in a preclinical model of post-menopausal breast cancer
Co-activator complexes facilitate transcriptional activation in part by interacting with chromatin remodeling and histone-modifying enzymes which render the target chromatin template permissive to transcriptional activation. One such protein is LSD1 [1], a flavin adenine dinucleotide-dependent amine oxidase that catalyzes methyl group removal from methylated histone H3 lysine 4 (H3K4) and H3 lysine 9 (H3K9) to effect transcriptional repression or activation, respectively (to avoid gene symbol and species ambiguity [2], all genes discussed in this editorial are accompanied by their unique National Center for Biotechnology Information (NCBI) GeneID: LSD1, known as KDM1 or AOF2; GeneID 23028; encodes lysine-specific histone demethylase 1)
Vadlamudi and colleagues [4] have shown that PELP1 is a dimethylated H3K4 (H3K4me2) and H3K9me2 reader and tilts LSD1 specificity toward H3K9me2, gearing LSD1 activity into transcriptional activation of ERα targets
Summary
LSD1, an epigenetic modifier, and PELP1, an estrogen receptor co-activator, integrate estrogen receptor ERα and HER2 receptor tyrosine kinase signaling to promote aromatase expression and hormone resistance in a preclinical model of post-menopausal breast cancer. In the previous issue of Breast Cancer Research, Vadlamudi and colleagues [1], from the University of Texas and from MD Anderson Cancer Center, implicate PELP1 ( known as HMX3 or MNAR; GeneID 27043; encodes proline-, glutamic acid-, and leucine-rich protein 1), a transcriptional co-activator that harbors neither DNA binding nor activation domains [4] and that couples LSD1 to ERα [5], in an ERα-PELP1-LSD1 axis of hormone resistance in breast cancer [1].
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