Mammary Tumorigenesis In C3hf Mouse Strains: Examination Of Germinal Mouse Mammary Tumor Viruses And The Int-1 And Int-2 Putative Proto-Oncogenes

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)


Microbiology and Immunology


Mouse Mammary Tumor Virus (MMTV) DNA and RNA sequences were examined in C3Hf/HeSed tissues. C3Hf/HeSed germline DNA contained the full-length MMTX Units Ib, II, and V, and the subgenomic MMTV Units 1 and IX. The EcoRI fragments (15.0 and 5.7 kbp) that contained Unit Ib were previously described as separate, subgenomic MMTV proviruses. The methylated-state of each full-length MMTV provirus was examined in DNA from C3Hf/HeSed tissues. Unit Ib contained HhaI and HpaII sensitive sites in spleen, mammary gland and mammary tumor DNA, but was completely methylated in liver DNA. Units II and V contained HhaI and HpaII sensitive sites in mammary gland and mammary tumor DNA, but the sites were extensively methylated in spleen and liver DNA. C3Hf/HeSed mammary glands contained MMTR RNA species of 9.0, 3.8 and 1.7 kb. Mammary tumors contained high levels of the 9.0 and 3.8 kb transcripts, but lacked the 1.7 kb species. A very low level of the 3.8 kb MMTV transcript was present in spleens. Livers lacked detectable MMTR RNA. These results implicate mammary tissue as the site of Unit V activation in the formation of MMTV virions. Three of eight C3Hf/HeSed mammary tumors contained somatically acquired MMTV proviruses. The region containing the putative mammary gland proto-oncogene int-1 was rearranged in one C3HF/HeSed mammary tumor. None of the mammary tumors examined contained int-1 transcripts. The region containing the putative mammary gland proto-oncogene int-2 did not appear rearranged in any C3Hf/HeSed mammary tumor; however, two tumors contained int-2 RNA transcripts. These results indicate that the int-1 and int-2 proto-oncogenes may play a role in some C3Hf/HeSed mammary tumors. MMTV sequences were examined in the C3Hf/Ki mouse strain. The full-length MMTV Units Ia, II, III, and IV in addition to the subgenomic MMTV Units I and IX, were germinally-transmitted in C3Hf/Ki DNA. The previously uncharacterized MMTV Unit Ia was contained in EcoRI fragments of 16.7 and 11.7 kbp. The 9.0, 3.8, and 1.7 kb MMTV RNA transcripts were present in C3Hf/Ki mammary glands. MMTV proviruses, in addition to the endogenous C3Hf/Ki MMTV complement, were not detected in mammary tumor DNA. The int-1 and int-2 regions did not appear reorganized, amplified, or expressed in C3Hf/Ki mammary tumors. These data suggest that the mechanism of mammary tumorigenesis in C3Hf/Ki mice may be different from that observed in C3Hf/He mice.


Biology, Molecular

Link to Full Text


Link to Full Text