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Human Breast Cancer Progression Can Be Regulated by Dominant Trans-Acting Factors in Somatic Cell Hybridization Studies¹

Department of Pathology [S. S., M. D. S., S. H. B.] and Revlon/UCLA Breast Canter [S. M. L., S. H. B.], UCLA School of Medicine, Los Angeles, California 90024, and Department of Medicine, UCI Clinical Cancer Center, Irvine, California 92717 [D. T. Y.]

Human breast cancer is often characterized by a progression to an ER (estrogen receptor)-negative, estrogen-independent, antiestrogen-resistant, EGFR (epidermal growth factor receptor)-positive, and highly metastatic phenotype. The molecular and biochemical mechanisms behind this progression are not well defined. Most studies of breast cancer have focused on one or another aspect of this progression but have not found a common pathway. By constructing stable and complete human-human somatic cell fusions between a highly metastatic, unifferentiated, ER-negative line of melanoma lineage and the estrogen-dependent, ER-positive MCF-7 line, this study produced hybrids that were ER negative, highly expressive of EGFR, estrogen independent, estrogen unresponsive, fully tumorigenic, and highly metastatic. ER negativity was on the basis of complete suppression of ER transcription as evidenced by Northern blot analysis and nuclear run-on assay, not on the basis of gene rearrangement. EGFR positivity was not due to gene amplification or rearrangement but rather to increased EGFR transcription. Mechanisms, including ras activation, fibroblast growth factor 4 expression, and human DNA methyl-transferase activation causing ER promoter methylation, which are respectively known to induce estrogen-independent growth, induce spontaneous metastasis, and decrease ER levels in breast carcinoma experimentally, were not mechanisms operating in the hybrids. This model demonstrates that many of the common denominators of human breast carcinoma progression can be regulated by dominant trans-acting factors.

¹ Supported by USPHS Grants CA40225 and CA01351; funds from the California Institute for Cancer Research, the Cancer Research Coordinating Committee, and the Jonsson Comprehensive Cancer Center; and the Cancer Center Core Grant, CA-16042. S. S. is a predoctoral trainee supported by the Mangasar Mangasarian Fellowship. M. D. S. is a predoctoral trainee supported by the USPHS National Institutional Research Service Award CA 09056. S. H. B. is a Recipient of a National Cancer Institute Research Career Development Award.

² To whom requests for reprints should be addressed, at Department of Pathology, UCLA School of Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90024.

Received 12/18/95. Accepted 5/31/96.

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