Differential functions of ERK1 and ERK2 in lung metastasis processes in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by metastasis, drug resistance and high rates of recurrence. With a lack or targeted therapies, TNBC is challenging to treat and carries a poor prognosis. Patients with TNBC tumors expressing high levels of ERK2 have a poorer prognosis than those with low ERK2-expressing tumors. The MAPK pathway is often found to be highly activated in TNBC, however the precise functions of the ERK isoforms (ERK1 and ERK2) in cancer progression have not been well defined. We hypothesized that ERK2, but not ERK1, promotes the cancer stem cell (CSC) phenotype and metastasis in TNBC. Stable knockdown clones of the ERK1 and ERK2 isoforms were generated in SUM149 and BT549 TNBC cells using shRNA lentiviral vectors. ERK2 knockdown significantly inhibited anchorage-independent colony formation and mammosphere formation, indicating compromised self-renewal capacity. This effect correlated with a reduction in migration and invasion. SCID-beige mice injected via the tail vein with ERK clones were employed to determine metastatic potential. SUM149 shERK2 cells had a significantly lower lung metastatic burden than control mice or mice injected with SUM149 shERK1 cells. The Affymetrix HGU133plus2 microarray platform was employed to identify gene expression changes in ERK isoform knockdown clones. Comparison of gene expression levels between SUM149 cells with ERK2 or ERK1 knockdown revealed differential and in some cases opposite effects on mRNA expression levels. Those changes associated with ERK2 knockdown predominantly altered regulation of CSCs and metastasis. Our findings indicate that ERK2 promotes metastasis and the CSC phenotype in TNBC.

Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis

“…The phosphorylated ERK1/2 then caused a significant increase in the mitosis of the cells. ERK1/2 has been linked to cancer progression and successful colony formation [ 114 , 115 ] In one study, Piezo1 was activated by stretching the substrate on which the cells were cultured, causing deformation of the cell membranes. The stretching of the cells induced a five-fold increase in proliferation [ 15 ].…”

Identification of nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer

“…Since the majority (∼75%) of TNBCs are transcriptomically classified as basal-like [9] , we utilized four basal-like human cell lines for these studies: HCC-1143, HCC-1187, MDA-468, and SUM-149. To best model aggressive, advanced disease, cell lines were chosen for their demonstrated ability to metastasize in vivo or relative chemoresistance in vitro [ 28 , 29 , 30 ]. The cytotoxic activity of 1363-drugs that have largely been FDA-approved for cancer/non-cancer indications was determined at a 10 µM dose; 68 therapeutic candidates that were strongly cytotoxic across the models were identified.…”

Unveiling Potential Mechanisms of Spatholobi Caulis against Lung Metastasis of Malignant Tumor by Network Pharmacology and Molecular Docking

“…MAPK1 (mitogen-activated protein kinase 1) and MAPK14 both belong to MAPK, which plays a vital role in the switch from extracellular signals to intracellular responses [ 39 ]. Gagliardi et al [ 40 ] observed that MAPK1 knockdown of SUM149 TNBC cells appeared restrained anchorage-independent colony formation and mammosphere formation, which indicated compromised capacity of self-renewal, migration, and invasion. Besides, the lung metastatic burden of SCID-beige mice injected via the tail vein with SUM149 shMAPK1 cells was predominantly lower than that of control mice.…”