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Stimulation of TPA-Responsive Element Activity by a Cooperative Action of Insulin and Estrogen in Human Breast Cancer Cells

Hubrecht Laboratory, Netherlands Institute for Developmental Biology 3584 CT Utrecht The Netherlands

Address requests for reprints to: Bart van der Burg, Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.

Abstract

Approximately one third of the human breast tumors are estradiol (E₂)-dependent in the initial stages of the disease. E₂ is thought to stimulate growth indirectly, through induced production of autocrine polypeptide growth factors. In this hypothesis constitutive production of such growth factors would lead to the loss of E₂ dependence, as associated with progression of the disease. Recent data, however, suggest that breast cancer cells do not react to the growth factors that they produce. Here we provide evidence that the direct stimulation of the c-fos proto-oncogene may be an important step in the stimulation by E₂ of the human breast cancer cell line MCF7. E₂ by itself, however, is poorly mitogenic, and it does not induce genes from the jun family, whose gene products are necessary for heterodimerization with the c-fos-encoded protein (Fos), leading to an important step in growth factor signalling pathways, stimulation of TPA-responsive element (TRE)-dependent transcriptional activity. In combination with insulin-like growth factors, that were found to be efficient inducers of c-jun in breast cancer cells, E₂ synergistically stimulates TRE activity and proliferation. These effects of E₂ on growth factor signalling pathways indicate that E₂ may directly induce the proliferation of MCF7 cells, independent from autocrine growth factors.

FOOTNOTES

This work was supported by the Netherlands Cancer Foundation.

Received for publication February 16, 1990. Revision received July 24, 1990. Accepted for publication August 1, 1990.

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