ITF2 is a target of CXCR4 in MDA-MB-231 breast cancer cells and is associated with reduced survival in estrogen receptor-negative breast cancer

Hitesh Appaiah, Poornima Bhat-Nakshatri, Rutika Mehta, Mangesh Thorat, Sunil Badve, Harikrishna Nakshatri

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

CXCR4, a chemokine receptor, plays an important role in breast cancer growth, invasion and metastasis. Transcriptional targets of CXCR4 signaling are not known. Microarray analysis of CXCR4-enriched and CXCR4-low subpopulations of MDA-MB-231 breast cancer cell line, which has constitutively active CXCR4 signaling network, revealed differential expression of ∼200 genes in the CXCR4-enriched subpopulation. ITF2 was one of the upregulated genes in CXCR4-enriched cells, which was investigated further. analysis of truly prognostic expression array datasets of primary breast tumors revealed higher ITF2 expression in estrogen receptor negative tumors correlating with reduced risk free and overall survival suggesting its relevance in breast cancer progression. CXCL12, a CXCR4 ligand, increased ITF2 expression in MDA-MB-231 cells. ITF2 is a basic helix-loop-helix transcription factor that controls epithelial-to-mesenchymal transition and the function of the ID family (inhibitor-of-differentiation) of transcription factors such as ID2. ID2 promotes differentiation of breast epithelial cells and its reduced expression in breast cancer is associated with unfavorable prognosis. Both CXCR4 and ITF2 repressed ID2 expression. Short interfering RNA against ITF2 reduced invasion of the CXCR4-enriched MDA-MB-231 subpopulation, whereas ITF2 overexpression restored the invasive capacity of MDA-MB-231 cells expressing CXCR4shRNa. In xenograft studies, CXCR4-enriched cells formed large tumors and exhibited significantly elevated lung metastasis. CXCR4shRNa cells overexpressing ITF2 displayed enhanced tumor growth. We propose that ITF2 is one of the CXCR4 targets, which is involved in CXCR4-dependent tumor growth and invasion of breast cancer cells.

Original languageEnglish (US)
Pages (from-to)600-614
Number of pages15
JournalCancer Biology and Therapy
Volume10
Issue number6
DOIs
StatePublished - Sep 15 2010

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Keywords

  • Breast cancer
  • CXCR4
  • ID2
  • Invasion
  • ITF2B

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology

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