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.

• Authors: Maria Gagliardi, Mary Kathryn Pitner, Jihyun Park, Xuemei Xie, Hitomi Saso, Richard A Larson, Rachel M Sammons, Huiqin Chen, Caimiao Wei, Hiroko Masuda, Gaurav Chauhan, Kimie Kondo, Debu Tripathy, Naoto T Ueno, Kevin N Dalby, Bisrat G Debeb, Chandra Bartholomeusz
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 8537 (05 22 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 32444778 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• RNA, Small Interfering
• MAPK1 protein, human
• MAPK3 protein, human
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Cell Movement
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (genetics, metabolism, secondary)
• Mice
• Mice, SCID
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, genetics, metabolism)
• Neoplastic Stem Cells (metabolism, pathology)
• Prognosis
• RNA, Small Interfering (genetics)
• Survival Rate
• Triple Negative Breast Neoplasms (genetics, metabolism, pathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays