HUMAN BREAST-CANCER PROGRESSION CAN BE REGULATED BY DOMINANT TRANS-ACTING FACTORS IN SOMATIC-CELL HYBRIDIZATION STUDIES

Human breast cancer is often characterized by a progression to an ER ( estrogen receptor)-negative, estrogen-independent, antiestrogen-resist ant, EGFR (epidermal growth factor receptor)-positive, and highly meta static 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 foun d a common pathway, By constructing stable and complete human-human so matic cell fusions between a highly metastatic, undifferentiated, ER-n egative line of melanoma lineage and the estrogen-dependent, ER-positi ve MCF-7 line, this study produced hybrids that were ER negative, high ly expressive of EGFR, estrogen independent, estrogen unresponsive, fu lly 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 rearr angement, EGFR positivity was not due to gene amplification or rearran gement but rather to increased EGFR transcription, Mechanisms, includi ng ms activation, fibroblast growth factor 4 expression, and human DNA methyltransferase activation causing ER promoter methylation, which a re respectively known to induce estrogen-independent growth, induce sp ontaneous metastasis, and decrease ER levels in breast carcinoma exper imentally, were not mechanisms operating in the hybrids, This model de monstrates that many of the common denominators of human breast carcin oma progression can be regulated by dominant trans-acting factors.