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This review summarizes recent advantages in understanding the mechanisms through which LSD1 controls
EMT in breast cancer, and discusses how these findings could be used to establish a new approach for
therapeutic intervention in breast cancer.

LSD1 MODULATE THE EMT PROCESS BY ITS PARTICIPATION IN DIFFERENT COMPLEXES
In human cancers, EMT contributes to tumor progression and invasion of surrounding tissues and
confers chemo-resistance. Morphological and phenotypic changes are orchestrated by transcriptional
[34]
reprogramming in which several transcription factors, known as EMT-TF , have a role in silencing of
epithelial genes (e.g., E-cadherin, Occludin) and in the activation of mesenchymal genes (e.g., N-cadherin,
[35]
Vimentin, Fibronectin) . EMT is characterized by reprogramming of epigenetic marks: following the
induction of the EMT by the transforming growth factor beta (TGF-β), a global increase of trimethylation in
[34]
[35]
H3K4 and H3K36 histones and a decrease in the dimethylation of H3K9 are observed . Mcdonald et al.
demonstrated that these epigenetic modifications depend largely on LSD1, and that loss of LSD1 functions
affects EMT-driven cell migration and chemo-resistance.

Taking in consideration different studies, it is clear that LSD1 may function as enhancer or inhibitor of EMT
functioning in a cell type-specific fashion, probably due to the cells genetic background and depending
[36]
on its interacting partners . A number of studies have described LSD1 as a critical player in epigenetic
reprogramming during EMT. Two independent reports demonstrated that LSD1 physically associates
with SNAIL1 (snail family transcriptional repressor 1) in breast cancer cells [15,34,37] . The members of the
SNAIL family of zinc finger transcription factors (Snail, Slug and Smuc) control the invasive phenotype
and metastasis in several types of cancers, included breast cancer. In the EMT pathway, SNAIL family
proteins repress the expression of epithelial genes, such as E-cadherin (CDH1), through an LSD1-dependent
molecular mechanism. It has been shown that LSD1, interacting with Snail, leads to CDH1 repression [15,34]
[Figure 2A]. In particular, it has been defined that the N-terminal SNAG domain of Snail is essential and
responsible for the interaction and recruitment of LSD1 to gene promoters. Notably, SNAG domain of
Snail1 resembles a histone H3-like structure, thus, it acts as a pseudo-substrate “hook” for LSD1 to recruit
it together with CoREST to the Snail1 target gene promoters [Figure 2A]. The inhibition of the Snail/Slug-
LSD1 interaction, using pharmacological LSD1 inhibitors or a cell-permeable peptide corresponding to the
[34]
SNAG domain of Slug, suppresses motility and invasiveness of breast cancer cells .

Notably, high expression of LSD1 or ERRα associates with breast cancer poor prognosis, decreased survival,
cancer progression and metastasis, and LSD1 has been found to protect the ERRα protein from proteasome
[38]
degradation . The ERRα-LSD1 complex regulates a subset of genes involved in migration and invasiveness
in breast cancer. The LSD1-ERRα complex binds the TSSs of common target genes and this interaction
[39]
induces LSD1 to demethylate H3K9 leading to transcriptional activation [Figure 2B].
Among co-regulated genes LSD1-ERRα enhances the expression of the matrix metalloproteinase 1 (MMP1),
a secreted protein involved in extracellular matrix degradation and cell invasion, and this can account for
[39]
the capacities of LSD1-ERRα to induce tumor progression .

Although the majority of work indicates that LSD1 is a key positive regulator of the EMT program, in
cooperation with other proteins such as the NuRD complex, it could promote opposite effects. It has been
reported that the LSD1/NuRD complex inhibits TGF-β signaling pathway, reducing breast cancer metastatic
[20]
potential [Figure 2C].
LSD1 has been found to have a role also as epigenetic regulator of EMT-TFs transcription factors expression
[34]
[SNAIL, zinc finger E-box-binding homeobox 1 (ZEB1) and ZEB2] . It has been reported that in breast
cancer stem cells LSD1 interacts with the Ubiquitously transcribed tetratricopeptide repeat, X chromosome