β2-Adrenergic Signalling Promotes Cell Migration by Upregulating Expression of the Metastasis-Associated Molecule LYPD3

Abstract

Metastasis is associated with poor prognosis in breast cancer. Although some studies suggest beta-blockers increase survival by delaying metastasis, others have been discordant. This study provides both insights into the anomalous findings and identifies potential biomarkers that may be treatment targets. Cell line models of basal-type and oestrogen receptor-positive breast cancer were profiled for basal levels of adrenoceptor gene/protein expression, and β2-adrenoceptor mediated cell behaviour including migration, invasion, adhesion, and survival in response to adrenoceptor agonist/antagonist treatment. Protein profiling and histology identified biomarkers and drug targets. Baseline levels of adrenoceptor gene expression are higher in basal-type rather than oestrogen receptor-positive cancer cells. Norepinephrine (NE) treatment increased invasive capacity in all cell lines but did not increase proliferation/survival. Protein profiling revealed the upregulation of the pro-metastatic gene Ly6/PLAUR Domain-Containing Protein 3 (LYPD3) in norepinephrine-treated MDA-MB-468 cells. Histology confirmed selective LYPD3 expression in primary and metastatic breast tumour samples. These findings demonstrate that basal-type cancer cells show a more aggressive adrenoceptor-β2-activated phenotype in the resting and stimulated state, which is attenuated by adrenoceptor-β2 inhibition. This study also highlights the first association between ADRβ2 signalling and LYPD3; its knockdown significantly reduced the basal and norepinephrine-induced activity of MCF-7 cells in vitro. The regulation of ADRβ2 signalling by LYPD3 and its metastasis promoting activities, reveal LYPD3 as a promising therapeutic target in the treatment of breast and other cancers.

Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival

“…LYPD3 is a protein that supports cell migration and may be involved in tumor progression [50]. Gruet et al [51] described that LYPD3 mRNA expression levels were low in normal tissues, but there is a significant (P < 0.001) over-expression of LYPD3 in several malignant tissues (breast cancer, cervical squamous cell carcinoma and endocervical adenocarcinoma, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic adenocarcinoma, testicular germ cell tumors and thymoma). This suggests that LYPD3 could be a potential therapeutic target in multiple different cancers.…”

Contribution of adrenergic mechanisms for the stress‐induced breast cancer carcinogenesis

“…Although pathways activated by α 2 ‐adrenergic receptors were shown to be involved in breast cancer metastasis (Gargiulo et al, 2014), most of the evidence point to the involvement of β‐adrenoceptors in the increase of the metastatic potential of breast tumor cells (Chang et al, 2016; Cui et al, 2019; Kamiya et al, 2019; Kim et al, 2016). Activation of β 2 ‐adrenoceptors promoted cell migration and invasion in several breast cancer cell lines by upregulating expression of the metastasis‐associated molecule Ly6/PLAUR Domain‐Containing Protein 3 (LYPD3) (Gruet et al, 2020). Furthermore, knockdown β 2 ‐adrenergic receptors is capable of blunt the stress‐enhanced metastatic burden, the number of mesenchymal‐like cells, and diminished cell invasion and expression of metalloproteinase 2 caused by β‐adrenoceptor agonists (Chang et al, 2016).…”

Cancer and Stress: Does It Make a Difference to the Patient When These Two Challenges Collide?

“…A recent study showed β-adrenergic receptor-driven metastasis in breast cancer cell lines. Norepinephrine treatment increased the invasive ability of cells, which also showed the upregulation of the pro-metastatic gene, LYPD3 [ 207 ]. Another study showed stress hormones decreased the deformability of breast cancer cells, making them stiffer and more invasive [ 208 ].…”