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Transcriptomic response of LSD1-UTX inhibitor on human breast cancer MCF7 cells

ABSTRACT: In many human cancers, including breast and prostate cancers, LSD1 and other lysine demethylases (KDMs), such as UTX, are co-expressed and co-localize with androgen receptors (AR) and estrogen receptors (ER), suggesting the potential use of hybrid molecules to target histone methylation and therefore to regulate/redirect hormone receptor signaling. Here, we report on the action of a pan-KDM inhibitor (3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. The 3324 hybrid molecule displays unique features not exhibited by moieties and well-characterized single inhibitors. The compound efficiently inhibits LSD1 as well as UTX enzymes, inducing significant growth arrest and apoptosis in hormone-responsive cells accompanied by a robust increase in H3K4me2 and H3K27me3. Treatment with 3324 reduces the level of ERα in breast and AR in prostate cancer cells at both transcriptional and non-transcriptional levels, acting as a selective endocrine receptor disruptor (SERD). Treatment with 3324 alters the methylation status of ER-regulated promoter regions, thereby affecting the transcription of genes involved in cell surveillance, death, and immune response. 3324 reduces cell proliferation in ex vivo breast cancers by interfering with hormone receptor signaling and/or receptor stability, as well as in cell models with acquired resistance to endocrine therapies (BT474, C4-2 and C4-2b). Similarly, 3324 displays tumor-selective potential in vivo, in both xenograft and chicken embryo models, with no toxicity and good oral efficacy. This multi-target approach may overcome potential mechanism(s) of resistance caused in part by redundancy and robustness of biological pathways, and find potential application in the treatment of resistant-to-therapy cancers such as those with acquired tamoxifen/enzalutamide resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE130067 | GEO | 2020/10/15

REPOSITORIES: GEO

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Project description:Current clinical guidelines suggest that breast cancers with low hormone receptor expression (LowHR) in 1% to 10% of tumor cells should be regarded as hormone receptor positive tumors. However, clinical data shows that patients with such tumors have a worse outcome compared to patients with hormone receptor expression above 10 %. Further, gene expression studies suggest that these tumors have a TNBC-like signature similar to triple negative breast cancers (TNBC). The goal of this study was to use DNA methylation-based classification to clarify the status for this infrequent but important patient subgroup. We performed whole genome DNA methylation profiling on 23 LowHR breast cancer specimens, including 13 samples with HER2 amplification and compared our results with a reference breast cancer cohort from The Cancer Genome Atlas. Unsupervised clustering and dimensionality reduction revealed that breast cancers with low hormone receptor expression that lacked HER2 amplification usually clustered with TNBC reference samples (8/10; “LowHR TNBC-like”). In contrast, most specimens with low hormone receptor expression and HER2 amplification grouped with hormone receptor positive cancers (11/13; “LowHR HRpos-like”). We observed highly similar DNA methylation patterns of LowHR TNBC-like samples and true TNBCs with almost no differential methylation. Furthermore, the Ki67 proliferation index of LowHR TNBC-like samples as well as clinical outcome parameters were more similar to TNBCs and differed from LowHR_HRpos-like cases. We here demonstrate that LowHR breast cancer comprises two molecularly distinct groups that can be separated by DNA methylation profiling. More clinical data is required for a definite classification of these tumors, but our data strongly suggests that LowHR TNBC-like samples are molecularly, histologically and clinically closely related to TNBC, while LowHR HRpos-like specimens are closely related to hormone receptor positive tumors.

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Transcriptomic response of LSD1-UTX inhibitor on human breast cancer MCF7 cells

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