RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells

Jessica L. Brusgard, Moran Choe, Saranya Chumsri, Keli Renoud, Alexander D. MacKerell, Marius Sudol, Antonino Passaniti

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Intratumoral heterogeneity and treatment resistance drive breast cancer (BC) metastasis and recurrence. The RUNX2 transcription factor is upregulated in early stage luminal BC. However, the precise mechanism by which RUNX2 regulates an oncogenic phenotype in luminal BCs remains an enigma. We show that RUNX2 is predictive of poor overall survival in BC patients. RUNX2 associated with the TAZ transcriptional co-activator to promote a tumorigenic phenotype that was inhibited by knockdown of TAZ. RUNX2 increased endogenous TAZ translocation to the nucleus, which was prevented by inhibiting RUNX2. RUNX2/TAZ interaction was associated with ectodomain shedding of an oncogenic soluble E-Cadherin fragment (sE-Cad), which is known to cooperate with human epidermal growth factor receptor-2 (HER2/ ErbB2) to increase BC growth. Neutralizing E-Cadherin antibodies or TAZ knockdown reduced the levels of sE-Cad in RUNX2-expressing BC cells and inhibited tumorsphere formation. RUNX2 expression also increased HER2-mediated tumorsphere size, which was reduced after treatment with the HER2-targeting agents Herceptin and lapatinib. These data support a novel role for RUNX2 in promoting an oncogenic phenotype in luminal BC in the context of TAZ, sE-Cad, and HER2. Using this signaling pathway to monitor BC cell oncogenic activity will accelerate the discovery of new therapeutic modalities to treat BC patients.

Original languageEnglish (US)
Pages (from-to)28132-28150
Number of pages19
JournalOncotarget
Volume6
Issue number29
DOIs
StatePublished - 2015

Fingerprint

Cadherins
Breast Neoplasms
Phenotype
Transcription Factors
Therapeutics
Neoplasm Metastasis
Recurrence
Survival
Antibodies
Growth

Keywords

  • Breast cancer
  • Therapeutics
  • Transcription factors
  • Tumorspheres

ASJC Scopus subject areas

  • Oncology

Cite this

RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells. / Brusgard, Jessica L.; Choe, Moran; Chumsri, Saranya; Renoud, Keli; MacKerell, Alexander D.; Sudol, Marius; Passaniti, Antonino.

In: Oncotarget, Vol. 6, No. 29, 2015, p. 28132-28150.

Research output: Contribution to journalArticle

Brusgard, Jessica L. ; Choe, Moran ; Chumsri, Saranya ; Renoud, Keli ; MacKerell, Alexander D. ; Sudol, Marius ; Passaniti, Antonino. / RUNX2 and TAZ-dependent signaling pathways regulate soluble E-Cadherin levels and tumorsphere formation in breast cancer cells. In: Oncotarget. 2015 ; Vol. 6, No. 29. pp. 28132-28150.
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