Catechol-O-methyl transferase suppresses cell invasion and interplays with MET signaling in estrogen dependent breast cancer

Abstract

Catechol-O-methyl transferase (COMT) is involved in detoxification of catechol estrogens, playing cancer-protective role in cells producing or utilizing estrogen. Moreover, COMT suppressed migration potential of breast cancer (BC) cells. To delineate COMT role in metastasis of estrogen receptor (ER) dependent BC, we investigated the effect of COMT overexpression on invasion, transcriptome, proteome and interactome of MCF7 cells, a luminal A BC model, stably transduced with lentiviral vector carrying COMT gene (MCF7-COMT). 2D and 3D assays revealed that COMT overexpression associates with decreased cell invasion (p < 0.0001 for Transwell assay, p < 0.05 for spheroid formation). RNA-Seq and LC-DIA-MS/MS proteomics identified genes associated with invasion (FTO, PIR, TACSTD2, ANXA3, KRT80, S100P, PREX1, CLEC3A, LCP1) being downregulated in MCF7-COMT cells, while genes associated with less aggressive phenotype (RBPMS, ROBO2, SELENBP, EPB41L2) were upregulated both at transcript (|log2FC|> 1, adj. p < 0.05) and protein (|log2FC|> 0.58, q < 0.05) levels. Importantly, proteins driving MET signaling were less abundant in COMT overexpressing cells, and pull-down confirmed interaction between COMT and Kunitz-type protease inhibitor 2 (SPINT2), a negative regulator of MET (log2FC = 5.10, q = 1.04−7). In conclusion, COMT may act as tumor suppressor in ER dependent BC not only by detoxification of catechol estrogens but also by suppressing cell invasion and interplay with MET pathway.

maGENEgerZ: An Efficient Artificial Intelligence-Based Framework Can Extract More Expressed Genes and Biological Insights Underlying Breast Cancer Drug Response Mechanism

“…In our study, we had two categories in Enrichr: ARCHS4 tissues and NCI-60 cancer cell lines, reporting one term (BREAST (BULK TISSUE)) in the former and three terms (MD-MB231, MCF7, and HS578T) in the latter. These breast cancer cell lines are well-established in biology and medicine when analyzing breast cancer, as in [97][98][99][100][101][102].…”

maGENEgerZ: An Efficient AI-Based Framework Can Extract More Expressed Genes and Biological Insights Underlying Breast Cancer Drug Response Mechanism

“…In our study, we had two categories in Enrichr: ARCHS4 Tissues and NCI-60 Cancer Cell Lines, reporting one term (BREAST (BULK TISSUE)) in the former and three terms (MD-MB231, MCF7, HS578T) in the latter. These breast cancer cell lines are well-established in biology and medicine when analysing breast cancer as in [98][99][100][101][102][103].…”

“…It is worth noting that we considered the following terms (i.e., breast cancer cell lines) within NCI-60 Cancer Cell Lines category: MD-MB231, MCF7, and HS578T. These breast cancer cell lines are well-established in biology and medicine when analysing breast cancer as in [89][90][91][92][93][94].…”

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough

“…Studies has indicated that the inhibition of COMT, particularly through the use of entacapone and tolcapone, can confer a safeguarding influence against amyloid‐induced toxicity (Kouter et al, 2023). Such drugs show competitive inhibition of the oligomerization and fibrillogenesis of Aβ and α‐synuclein, while also exhibiting protective effects against extracellular toxicity resulting from the aggregation of these pathological proteins (Janacova et al, 2023). The efficacy of Entacapone and Tolcapone in reducing homocysteine levels has been established, suggesting their potential utility in the management of hyperhomocysteinemia subsequent to L‐dopa therapy (Kouter et al, 2023).…”