Differentiation-dependent expression of provirus-activated int-1 oncogene in clonal cell lines derived from a mouse mammary tumor.
The int-1 mammary oncogene is frequently activated by proviral insertion in mouse mammary tumors. To characterize the target cell for the oncogenic action of int-1, we have isolated permanent cell lines with distinct morphologies and differentiation characteristics, starting from a tumor with a rearranged int-1 gene. Polygonal cells had retained many differentiation markers of epithelial cells and produced adenocarcinomas upon transplantation in syngenic mice. Sphere-forming-cuboidal cells are poorly differentiated and produced anaplastic tumors. Cuboidal and elongated cells were negative for epithelial markers. Cuboidal cells were poorly tumorigenic, but elongated cells produced highly malignant sarcoma-like tumors. In all lines, the int-1 gene was identically rearranged due to insertion of proviral DNA of the Mouse Mammary Tumor Virus, but the expression of int-1 varied with the state of differentiation of the cells. Polygonal cells contained relatively high levels of int-1 RNA, which were not influenced by steroid hormones. In the sphere-forming-cuboidal cells, expression of int-1 was low but inducible by dexamethasone. In the cuboidal and elongated cells no expression of int-1 was detectable, showing that the continued expression of int-1 was not required for progression to more malignant cells. By immunoprecipitation, two int-1 protein species, of 42 and 40 kD were identified in polygonal and in sphere-forming-cells but not in the culture media.
Schuuring
E
E
Division of Molecular Biology, Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam.
van der Leede
B J
BJ
Willems
R
R
Daams
H
H
van der Valk
M
M
van de Vijver
M
M
van Leeuwen
F
F
Sonnenberg
A
A
Nusse
R
R
D000230:Adenocarcinoma / Q000235:genetics* / Q000382:microbiology / Q000473:pathology / Q000648:ultrastructure; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002999:Clone Cells; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D015870:Gene Expression; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000382:microbiology / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008809:Mice, Inbred C3H; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D009857:Oncogenes; D011533:Proviruses / Q000235:genetics*
D004273:DNA, Neoplasm; D009856:Oncogene Proteins, Viral