Abstract
Macrophages play an important role in regulating the tumor microenvironment (TME). Here we show that classical (M1) macrophage polarization reduced expression of LSD1, nuclear REST corepressor 1 (CoREST), and the zinc finger protein SNAIL. The LSD1 inhibitor phenelzine targeted both the flavin adenine dinucleotide (FAD) and CoREST binding domains of LSD1, unlike the LSD1 inhibitor GSK2879552, which only targeted the FAD domain. Phenelzine treatment reduced nuclear demethylase activity and increased transcription and expression of M1-like signatures both in vitro and in a murine triple-negative breast cancer model. Overall, the LSD1 inhibitors phenelzine and GSK2879552 are useful tools for dissecting the contribution of LSD1 demethylase activity and the nuclear LSD1-CoREST complex to switching macrophage polarization programs. These findings suggest that inhibitors must have dual FAD and CoREST targeting abilities to successfully initiate or prime macrophages toward an anti-tumor M1-like phenotype in triple-negative breast cancer.
Highlights
Breast cancer is the most common female cancer worldwide [1]
We previously showed that Lysine-specific demethylase 1 (LSD1) modulates epithelial to mesenchymal transition in cancer stem cell (CSC) and that LSD1 inhibition promotes an M1-type response in an immune-deficient mouse cancer xenograft model [22]
We examined the effects of epigenetic inhibition of LSD1 on macrophage phenotype in vitro and in vivo using two different LSD1 inhibitors: GSK, which only binds to the flavin adenine dinucleotide (FAD) domain, and phenelzine, which can bind to the FAD domain and disrupt the LSD1-CoREST complex
Summary
Breast cancer is the most common female cancer worldwide [1]. The triple-negative subtype of breast cancer (TNBC) accounts for 15–20% of cases [2, 3] and is characterized by an absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression [3,4,5]. TNBC patients have a worse prognosis than patients with other breast cancer subtypes, not least because they do not have the targets and so do not respond to hormonal or HER2-targeting therapies. TNBCs have a high immune cell infiltrate compared to other breast cancer subtypes, but these immune cells are often functionally impaired [8, 9]. The tumor microenvironment (TME) of any cancer contains a complex mixture of immune cells with both pro- and anti-tumor properties. Lipopolysaccharide (LPS) and IFN-γinduced M1 macrophages secrete pro-inflammatory cytokines and reactive oxygen/nitrogen species that contribute to tumor cell cytotoxicity. IL-4- and IL-13-induced M2 macrophages produce anti-inflammatory cytokines that can suppress other immune cells in the TME and promote tumor progression [12,13,14]
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