Integration of ERα-PELP1-HER2 signaling by LSD1 (KDM1A/AOF2) offers combinatorial therapeutic opportunities to circumventing hormone resistance in breast cancer

The fact that the majority of breast cancers express estrogen receptor-alpha (ERα) and thus are estrogen-dependent is both a curse and a blessing. It is a blessing because ERα is a well-defined molecular target that can be efficiently inhibited by drugs in adjuvant therapy to avert relapse as well as in the palliative treatment of advanced disease. It is a curse because a significant percentage of patients fail to respond to treatment and end up relapsing. Thus, for instance, although the ERα antagonist tamoxifen has proven to be one of the most successful drugs to be developed for the targeted therapy of cancer, more than half of patients with ERα-positive breast cancer show intrinsic or acquired tamoxifen resistance. Therefore, the mechanisms of ERα pathway drug resistance and the means of circumventing them represent high-priority fields in breast cancer research.A predominant mechanism by which ERα drives breast cancer pathogenesis is the so-called nuclear genomic pathway. In this process, ERα recruits co-activator complexes to gene targets to potentiate their transcription. 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, also known as KDM1 or AOF2; GeneID 23028; encodes lysine-specific histone demethylase 1). LSD1 demethylates H3K9 of ERα chromatin targets in an estrogen-dependent manner, leading to hydrogen peroxide production and recruitment of 8-oxoguanine