Cathepsin V suppresses GATA3 protein expression in luminal A breast cancer

Abstract

Background Lysosomal cysteine protease cathepsin V has previously been shown to exhibit elevated expression in breast cancer tissue and be associated with distant metastasis. Research has also identified that cathepsin V expression is elevated in tumour tissues from numerous other malignancies, but despite this, there has been limited examination of the function of this protease in cancer. Here we investigate the role of cathepsin V in breast cancer in order to delineate the molecular mechanisms by which this protease contributes to tumourigenesis. Methods Lentiviral transductions were used to generate shRNA cell line models, with cell line validation undertaken using RQ-PCR and Western blotting. Phenotypic changes of tumour cell biology were examined using clonogenic and invasion assays. The relationship between GATA3 expression and cathepsin V was primarily analysed using Western blotting. Site-directed mutagenesis was used to generate catalytic mutant and shRNA-resistant constructs to confirm the role of cathepsin V in regulating GATA3 expression. Results We have identified that elevated cathepsin V expression is associated with reduced survival in ER-positive breast cancers. Cathepsin V regulates the expression of GATA3 in ER-positive breast cancers, through promoting its degradation via the proteasome. We have determined that depletion of cathepsin V results in elevated pAkt-1 and reduced GSK-3β expression, which rescues GATA3 from proteasomal degradation. Conclusions In this study, we have identified that cysteine protease cathepsin V can suppress GATA3 expression in ER-positive breast cancers by facilitating its turnover via the proteasome. Therefore, targeting cathepsin V may represent a potential therapeutic strategy in ER-positive breast cancers, by restoring GATA3 protein expression, which is associated with a more favourable clinical outcome.

Upregulated GATA3/miR205-5p Axis Inhibits MFNG Transcription and Reduces the Malignancy of Triple-Negative Breast Cancer

“…Additionally, the overexpression of GATA3 in BT-549 and MDA-MB-231 cells significantly reduced cell migration in vitro and impaired mesenchymal phenotypes, while the opposite results were found following GATA3 knockdown. Our in vitro findings are consistent with the previous reports that GATA3 negatively regulates TNBC progression [20,34,35]. To further clarify how GATA3 diminishes TNBC aggressiveness, we demonstrated here that MFNG is a direct target of GATA3 and that loss of MFNG is associated with less invasiveness and TNBC development in vitro.…”

Key Matrix Remodeling Enzymes: Functions and Targeting in Cancer

“…In breast invasive ductal carcinoma (IDC) patients, analysis of tissue specimens by IHC revealed that CTSL is expressed in advanced tumor stage patients, CTSB is found in ERα+ tissues with poor disease-free survival (DFS) rates, CTSK is expressed in ERα+/PR+ tumors and, finally, CTSD expression associates with poor prognosis, high incidence of metastasis, especially to the chest, and low DFS rates [ 181 ]. Likewise, CTSV expression favors distant metastasis, hence low survival rates in ERα+ breast cancer, as it facilitates cell proliferation and invasion while attenuating the expression of GATA3 through PI3K-AKT-GSK3β pathway [ 170 ] ( Figure 2 ). In addition, in MCF-7 breast cancer cells CTSB is upregulated while it suppresses E-cadherin.…”

Prognostic signature for hepatocellular carcinoma based on 4 pyroptosis-related genes

“…Among the four key PRGs obtained, cathepsin V (CTSV) promotes the proliferation and invasion of tumour cells in breast cancer [13] and colorectal cancer [14], but its role in liver cancer is unclear. CXCL8/IL-8 is a well-known chemokine that mediates cancer cell motility, invasion and metastasis by promoting epithelial-mesenchymal transition (EMT) [15], and IL-8 has been found to increase cancer proliferation in vitro [16].…”