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

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

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish (US)
Article number8537
JournalScientific reports
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • General

MD Anderson CCSG core facilities

  • Advanced Technology Genomics Core
  • Biostatistics Resource Group
  • Flow Cytometry and Cellular Imaging Facility
  • Research Animal Support Facility
  • Tissue Biospecimen and Pathology Resource
  • Cytogenetics and Cell Authentication Core

Fingerprint

Dive into the research topics of 'Differential functions of ERK1 and ERK2 in lung metastasis processes in triple-negative breast cancer'. Together they form a unique fingerprint.

Cite this