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Loss of growth responsiveness to epidermal growth factor and enhanced production of alpha‐transforming growth factors in ras‐transformed mouse mammary epithelial cells

A mouse mammary epithelial cell line, NMuMG, exhibits a low capacity to grow in semisolid medium as colonies and it is not tumorigenic in nude mice. In contrast, NMuMG cells which have been transformed by an activated c‐Harvey ras proto‐oncogene, NMuMG/rasH, or by the polyoma middle T‐transforming gene, NMuMG/pyt, are able to grow in soft agar and, when injected into nude mice, produce undifferentiated carcinomas. Human epidermal growth factor (EGF) or human alpha‐transforming growth factor (α TGF) can stimulate, in a dose‐dependent fashion, the anchorage‐independent growth of NMuMG and NMuMG/pyt cells in soft agar but fail to enhance the anchorage‐independent growth of the NMuMGrasH cells. Likewise, human EGF or human αTGF is also able to stimulate the anchorage‐dependent growth of normal NMuMG cells and NMuMG/pyt cells in a serum‐free medium supplemented with insulin, transferrin, fetuin, and laminin, or in medium containing low concentrations of serum, wheres these same growth factors under comparable culture conditions have little or no effect upon the anchorage‐dependent growth of the ras‐transformed NMuMG‐rasH cells. The biological refractoriness of the NMuMG/rasH cells to human EGF or human α TGF is reflected by a reduction in the total number of cell surface receptors for EGF and by an absence of a high‐affinity population of binding sites for mouse [125l]EGF on these cells as compared to the NMuMG or NMuMG/pyt cells. In addition, concentrated conditioned medium (CM) obtained from NMuMG/rasH and NMuMG/pyt cells contains a relatively higher amount of biologically active TGFs than CM obtained from comparably treated NMuMG cells as measured by the ability to induce the anchorage‐independent growth of normal rat kidney cells in soft agar. The higher levels of biologically active TGFs found in the CM from the transformed cells relative to the NMuMG cells is paralleled by a corresponding increase in the CM from these cells in the amount of immunoreactive αTGF, by an increase in the amount of EGF receptor‐competing activity, and by an increase in the levels of αTGF mRNA in the NMuMG/rasH cells. These results demonstrate that mammary epithelial cells which have been transformed by an activated ras proto‐oncogene, but not by the polymoa middle T‐transforming gene, become unresponsive to exogenous EGF or αTGF. The growth refractoriness of the NMuMG/rasH cells to exogenous EGF may be due to the reduction in the number and affinity of EGF receptors on these cells and because of an increased capacity of these cells to synthesize and secrete their own αTGFs.