Spontaneous progression of hyperplastic outgrowths of the D1 lineage to mammary tumors: expression of mouse mammary tumor virus and cellular proto-oncogenes.
Mammary cancer in mice is characterized by progression through defined stages of preneoplasia, with the most common preneoplastic stage being the hyperplastic alveolar nodule (HAN). We determined the relative levels of RNA expression of various cellular proto-oncogenes and endogenous mouse mammary tumor virus genes in outgrowths and tumors of three sublines of the transplantable D1 HAN preneoplastic outgrowth line. The three sublines differed in relative tumor-producing capabilities. Subline D1B produced a high incidence of tumors with short latency periods, whereas sublines D1C and D1D produced low incidences of tumors with long latency periods. No consistent alteration in proto-oncogene expression correlated with relative tumorigenicity, although tumors frequently contained higher levels of one or more proto-oncogene transcripts as compared with preneoplastic tissue. Slightly elevated (2- to 6-fold) levels of different oncogene transcripts were detected in 13 of 17 tumors as compared with outgrowth tissue, including abl (2 tumors), fps (5 tumors), Ha-ras (6 tumors), and Ki-ras (8 tumors). One tumor contained 45 times more Ki-ras-specific RNA than outgrowth tissue because of a comparable amplification of Ki-ras DNA sequences. Elevated levels of Ha-ras occurred more frequently in tumors of a high-incidence subline than in a less-aggressive subline (5/10 vs 1/7), but this difference was not statistically significant. However, consistent changes in MMTV expression accompanied progression from preneoplastic tissues to mammary tumors. All 17 tumors displayed reduced levels of the MMTV-specific long terminal repeat (LTR) transcript (1.6 kb) as compared with HAN tissue; tumors with moderate levels of LTR transcript expressed the 3.8-kb envelope message as well, one not detected in HANs. Expression of the LTR transcript is apparently influenced by factors in addition to the methylation status of endogenous mouse mammary tumor virus genes, which was similar in outgrowths and tumors. As the survey of representative proto-oncogenes failed to identify a uniform change between HAN and tumors, it is likely that other genes are involved in tumor progression in the mammary gland.
Knepper
J E
JE
Division of Molecular Virology, Baylor College of Medicine, Houston, Texas.
Kittrell
F S
FS
Medina
D
D
Butel
J S
JS
D000818:Animals; D015342:DNA Probes; D004273:DNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D004279:DNA, Viral / Q000235:genetics / Q000302:isolation & purification; D015870:Gene Expression; D005814:Genes, Viral; D006965:Hyperplasia; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000382:microbiology / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D011519:Proto-Oncogenes
D015342:DNA Probes; D004273:DNA, Neoplasm; D004279:DNA, Viral