c-Myc is a major mediator of the synergistic growth inhibitory effects of retinoic acid and interferon in breast cancer cells

Yongfeng Shang, Craig R. Baumrucker, Michael Henry Green

Research output: Contribution to journalArticle

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Abstract

The molecular signaling events involved in the inhibition of breast cancer cell growth by retinoic acid and interferon-α were investigated. All- trans-retinoic acid and interferon-α acted synergistically to inhibit growth of both the estrogen receptor-positive breast cancer cell line MCF-7 and the estrogen receptor-negative line BT-20. In MCF-7 cells, all-trans-retinoic acid potentiated the effects of interferon-α by up-regulating the expression of the RNA-dependent protein kinase (PKR). Consequently, the synergism between all-trans-retinoic acid and interferon-α down-regulated the expression of c-Myc, but not its functional partner, Max. Transfection of MCF-7 cells with a dominant-negative mutant of PKR relieved c-Myc down- regulation and cell growth inhibition, indicating that PKR is directly involved in c-Myc down-regulation and that c-Myc down-regulation is responsible for the inhibition of cell growth. Corresponding with c-Myc down- regulation, c-Myc·Max heterodimers hound to their consensus DNA sequence were undetectable in cells treated with all-trans-retinoic acid and interferon-α, indicating diminished c-Myc functionality. When c-Myc was overexpressed ectopically via a c-Myc expression vector, MCF-7 cells became resistant to growth inhibition by all-trans-retinoic acid plus interferon- α. These experiments define the following pathway as a major pathway in the synergistic growth inhibition of MCF-7 cells by all-trans-retinoic acid plus interferon-α: all-trans-retinoic acid + interferon-α → double-stranded RNA-dependent protein kinase → ↓ c-Myc → cell growth inhibition.

Original languageEnglish (US)
Pages (from-to)30608-30613
Number of pages6
JournalJournal of Biological Chemistry
Volume273
Issue number46
DOIs
StatePublished - Nov 13 1998

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Tretinoin
Interferons
Cells
Breast Neoplasms
MCF-7 Cells
Cell growth
eIF-2 Kinase
Growth
Down-Regulation
Estrogen Receptors
Double-Stranded RNA
DNA sequences
Consensus Sequence
Transfection
Cell Line

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Shang, Yongfeng ; Baumrucker, Craig R. ; Green, Michael Henry. / c-Myc is a major mediator of the synergistic growth inhibitory effects of retinoic acid and interferon in breast cancer cells. In: Journal of Biological Chemistry. 1998 ; Vol. 273, No. 46. pp. 30608-30613.
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c-Myc is a major mediator of the synergistic growth inhibitory effects of retinoic acid and interferon in breast cancer cells. / Shang, Yongfeng; Baumrucker, Craig R.; Green, Michael Henry.

In: Journal of Biological Chemistry, Vol. 273, No. 46, 13.11.1998, p. 30608-30613.

Research output: Contribution to journalArticle

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