Mammary gland tumor in transgenic mice expressing targeted beta-casein/HPV16E6 fusion gene.
The human papillomaviruses (HPV)-16 and HPV-18 referred to as high-risk HPVs are strongly associated with anogenital malignancies as well as benign epithelial cysts. It has been demonstrated that transgenic mice carrying HPV-16 E6-E7 under the control of the MMTV LTR developed malignant tumors including salivary gland carcinoma, lymphoma, skin histiocytomas and testicular tumors in a non-mammary gland specific manner. Another regulatory unit of rat beta-casein gene can confer the expression of fusion gene preferentially in the mammary glands of transgenic mice in a developmentally regulated manner. In order to generate mammary tumor formation in transgenic mice directing HPV16E6 gene alone into the mammary gland, this regulatory unit was fused to the E6 gene of HPV-16 type to constructing fusion gene. By screening 51 newborn founder transgenic mice, three mice carrying transgenes were identified. One line termed TG32 developed in a mammary gland tumor with large subcutaneous mass in the left rib region at 17 months of age. The levels of E6 transcript in the mass-tumor of TG32 line were lower than those in non-tumor mammary gland of identical TG32 and of TG250. In each tissue of TG32 line, high expression of E6 transcript was detected both in the mammary gland and brain. Histological analysis showed that cells from mammary gland tumor of the TG32 line had also hyperplasia appearance, with irregular or increased total number of mitotic rate. These observations suggest that developing phenotype and the level of E6 transcripts in the process of malignant transformation may have different mechanisms involving the capacity to bind and destabilize p53, although for confirmation it is necessary to investigate many more transgenic mice.
Hwang
D Y
DY
Division of Laboratory Animal Resources, Korea Food and Drug Administration, National Institute of Toxicological Research, Seoul 122-704, Korea.
Chae
K R
KR
Shin
D H
DH
Jang
I S
IS
Hwang
J H
JH
Kim
Y J
YJ
Cho
J Y
JY
Kim
B J
BJ
Goo
J S
JS
Lim
C J
CJ
Kim
C K
CK
Cho
Y Y
YY
Paik
S G
SG
Kim
Y K
YK
Cho
J S
JS
D000818:Animals; D002364:Caseins / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics; D005260:Female; D005813:Genes, Synthetic; D008321:Mammary Glands, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000502:physiology; D009928:Organ Specificity; D027383:Papillomaviridae / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002364:Caseins; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53