Expression of transforming growth factor α antisense mRNA inhibits the estrogen-induced production of TGFa and estrogen-induced proliferation of estrogen-responsive human breast cancer cells

N. J. Kenney, T. Saeki, M. Gottardis, N. Kim, P. Garcia-Morales, M. B. Martin, N. Normanno, F. Ciardiello, A. Day, M. L. Cutler, D. S. Salomon

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Abstract

To ascertain if 17β-estradiol (E2)-induced proliferation could be attenuated by blocking the expression of endogenous transforming growth factor α (TGFα), estrogen receptor (ER)-positive, estrogen-responsive MCF-7 or ZR-75-1 cells and ER-negative, estrogen-nonresponsive MDA-MB-468 or HS-578T cells were infected with a recombinant amphotropic, replication-defective retroviral expression vector containing a 435 base pair (bp) Apal-fco R1 coding fragment of the human TGFα cDNA oriented in the 3′ to 5′ direction and under the transcriptional control of an internal heavy metal-inducible mouse metallothionein (MT-1) promoter and containing the neomycin (neo) resistance gene. E2-stimulated expression of endogenous TGFα mRNA was inhibited by 4-5-fold, and the production of TGFα protein was inhibited by 50-80% when M-1 mass-infected MCF-7 or MZ-1 mass-infected ZR-75-1 cells were treated with 0.75-1 μCdCl2, whereas in comparably treated parental MCF-7 or ZR-75-1 cells there was no significant effect upon these parameters. E2-stimulated anchorage-dependent growth (ADG) and anchorage-independent growth (AIG) of the M-1 or MZ-1 cells was inhibited by 60-90% following CdCl2 treatment. In contrast, neither the ADG nor AIG of the parental noninfected MCF-7 or ZR-75-1 cells that were maintained in the absence or presence of E2 was affected by comparable concentrations of CdCl2 The ADG and AIG of TGFα antisense MD-1 mass-infected MDA-MB-468 cells that express high levels of endogenous TGFα mRNA were also inhibited by 1 μM CdCl2, whereas the ADG and AIG of MH-1 mass-infected HS-578T cells, a TGFα-negative cell line, were unaffected by CdCl2 treatment. These results suggest that TGFα may be one important autocrine intermediary in regulating estrogen-induced cell proliferation.

Original languageEnglish
Pages (from-to)497-514
Number of pages18
JournalJournal of Cellular Physiology
Volume156
Issue number3
Publication statusPublished - Sep 1993

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ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry
  • Physiology

Cite this

Kenney, N. J., Saeki, T., Gottardis, M., Kim, N., Garcia-Morales, P., Martin, M. B., Normanno, N., Ciardiello, F., Day, A., Cutler, M. L., & Salomon, D. S. (1993). Expression of transforming growth factor α antisense mRNA inhibits the estrogen-induced production of TGFa and estrogen-induced proliferation of estrogen-responsive human breast cancer cells. Journal of Cellular Physiology, 156(3), 497-514.