Epidermal growth factor receptor, but not c-erbB-2, activation prevents lactogenic hormone induction of the beta-casein gene in mouse mammary epithelial cells.
The HC11 cell line was isolated from mammary gland cells of pregnant mice. The cells displayed a normal phenotype and retained some characteristics of mammary epithelial cell differentiation. After treatment with the lactogenic hormones prolactin and glucocorticoids, the HC11 cells expressed the milk protein beta-casein. Various oncogenes were transfected and expressed in HC11 cells. The oncogenes were tested for their transformation ability and for their effects upon the differentiation of the HC11 cells. All of the oncogenes tested, including activated human Ha-ras, human transforming growth factor-alpha, activated rat neuT, and human c-erbB-2 activated by a point mutation in the transmembrane domain, caused transformation of the HC11 cells, as shown by tumor formation in nude mice. HC11 cells expressing the neuT and activated c-erbB-2 genes synthesized beta-casein in response to lactogenic hormones, whereas those expressing the Ha-ras or transforming growth factor-alpha oncogenes were no longer able to respond to the lactogenic hormones. This inhibition of beta-casein production occurs at the transcriptional level and in the transforming growth factor-alpha-transformed cells is due to an autocrine mechanism involving the activation of the epidermal growth factor receptor. This suggests that, although the c-erbB-2 and epidermal growth factor receptors are structurally quite similar, their activation has different effects upon mammary epithelial cell differentiation.
Friedrich Miescher Institute, Basel, Switzerland.
N E
NE
Hynes
D
D
Taverna
I M
IM
Harwerth
F
F
Ciardiello
D S
DS
Salomon
T
T
Yamamoto
B
B
Groner
D000818:Animals; D000911:Antibodies, Monoclonal; D002364:Caseins / Q000235:genetics*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells; D003907:Dexamethasone / Q000494:pharmacology*; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004848:Epithelium; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D005796:Genes; D007328:Insulin / Q000494:pharmacology; D008321:Mammary Glands, Animal; D051379:Mice; D010957:Plasmids; D011247:Pregnancy; D011388:Prolactin / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics*; D011519:Proto-Oncogenes; D051381:Rats; D014162:Transfection; D015291:Transforming Growth Factors / Q000096:biosynthesis / Q000235:genetics
D000911:Antibodies, Monoclonal; D002364:Caseins; D007328:Insulin; D011518:Proto-Oncogene Proteins; D004815:Epidermal Growth Factor; D015291:Transforming Growth Factors; D003907:Dexamethasone; D011388:Prolactin; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases