Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype
<p>Abstract</p> <p>Background</p> <p><it>MMTV-Wnt1 </it>transgenic mice develop mammary hyperplasia early in development, followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepith...
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| Format: | Article |
| Language: | English |
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BMC
2004-06-01
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| Series: | BMC Medicine |
| Online Access: | http://www.biomedcentral.com/1741-7015/2/24 |
| _version_ | 1819033582482489344 |
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| author | Li Yi Podsypanina Katrina Varmus Harold E |
| author_facet | Li Yi Podsypanina Katrina Varmus Harold E |
| author_sort | Li Yi |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p><it>MMTV-Wnt1 </it>transgenic mice develop mammary hyperplasia early in development, followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepithelial cells. The occurrence of tumors is accelerated in experiments that activate <it>FGF </it>proto-oncogenes or remove the tumor suppressor genes <it>Pten </it>or <it>P53</it>, implying that secondary oncogenic events are required for progression from mammary hyperplasia to carcinoma. It is not known, however, which oncogenic pathways contribute to <it>Wnt1</it>-induced tumorigenesis – further experimental manipulation of these mice is needed. Secondary events also appear to be required for mammary tumorigenesis in <it>MMTV-Neu </it>transgenic mice because the transgene in the tumors usually contains an acquired mutation that activates the Neu protein-tyrosine kinase.</p> <p>Methods</p> <p>cDNA or DNA from the mammary glands and mammary tumors from <it>MMTV-Wnt1</it>, <it>MMTV-Wnt1/p53</it><sup>-/-</sup>, <it>MMTV-Neu </it>transgenic mice, and newly generated <it>MMTV-Wnt1/MMTV-Neu </it>bitransgenic mice, was sequenced to seek activating mutations in <it>H-Ras</it>, <it>K-Ras</it>, and <it>N-Ras </it>genes, or in the <it>MMTV-Neu </it>transgene. In addition, tumors from bitransgenic animals were examined to determine the cellular phenotype.</p> <p>Results</p> <p>We found activating mutations at codons 12, 13, and 61 of <it>H-Ras </it>in just over half of the mammary tumors in <it>MMTV-Wnt1 </it>transgenic mice, and we confirmed the high frequency of activating mutations of <it>Neu </it>in tumors in <it>MMTV-Neu </it>transgenic mice. Tumors appeared earlier in bitransgenic <it>MMTV-Wnt1/MMTV-Neu mice</it>, but no <it>Ras </it>or <it>MMTV-Neu </it>mutations were found in these tumors, which were phenotypically similar to those arising in <it>MMTV-Wnt1 </it>mice. In addition, no <it>Ras </it>mutations were found in the mammary tumors that arise in <it>MMTV-Wnt1 </it>transgenic mice lacking an intact <it>P53 </it>gene.</p> <p>Conclusions</p> <p>Tumorigenic properties of cells undergoing functionally significant secondary mutations in <it>H-Ras </it>or the <it>MMTV-Neu </it>transgene allow selection of those cells in <it>MMTV-Wnt1 </it>and <it>MMTV-Neu </it>transgenic mice, respectively. Alternative sources of oncogenic potential, such as a second transgenic oncogene or deficiency of a tumor suppressor gene, can obviate the selective power of those secondary mutations. These observations are consistent with the notion that somatic evolution of mouse mammary tumors is influenced by the specific nature of the inherited cancer-promoting genotype.</p> |
| first_indexed | 2024-12-21T07:20:08Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-12-21T07:20:08Z |
| publishDate | 2004-06-01 |
| publisher | BMC |
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| series | BMC Medicine |
| spelling | doaj.art-938d92ab08b9477a978449d6ee5920942022-12-21T19:11:48ZengBMCBMC Medicine1741-70152004-06-01212410.1186/1741-7015-2-24Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotypeLi YiPodsypanina KatrinaVarmus Harold E<p>Abstract</p> <p>Background</p> <p><it>MMTV-Wnt1 </it>transgenic mice develop mammary hyperplasia early in development, followed by the appearance of solitary mammary tumors with a high proportion of cells expressing early lineage markers and many myoepithelial cells. The occurrence of tumors is accelerated in experiments that activate <it>FGF </it>proto-oncogenes or remove the tumor suppressor genes <it>Pten </it>or <it>P53</it>, implying that secondary oncogenic events are required for progression from mammary hyperplasia to carcinoma. It is not known, however, which oncogenic pathways contribute to <it>Wnt1</it>-induced tumorigenesis – further experimental manipulation of these mice is needed. Secondary events also appear to be required for mammary tumorigenesis in <it>MMTV-Neu </it>transgenic mice because the transgene in the tumors usually contains an acquired mutation that activates the Neu protein-tyrosine kinase.</p> <p>Methods</p> <p>cDNA or DNA from the mammary glands and mammary tumors from <it>MMTV-Wnt1</it>, <it>MMTV-Wnt1/p53</it><sup>-/-</sup>, <it>MMTV-Neu </it>transgenic mice, and newly generated <it>MMTV-Wnt1/MMTV-Neu </it>bitransgenic mice, was sequenced to seek activating mutations in <it>H-Ras</it>, <it>K-Ras</it>, and <it>N-Ras </it>genes, or in the <it>MMTV-Neu </it>transgene. In addition, tumors from bitransgenic animals were examined to determine the cellular phenotype.</p> <p>Results</p> <p>We found activating mutations at codons 12, 13, and 61 of <it>H-Ras </it>in just over half of the mammary tumors in <it>MMTV-Wnt1 </it>transgenic mice, and we confirmed the high frequency of activating mutations of <it>Neu </it>in tumors in <it>MMTV-Neu </it>transgenic mice. Tumors appeared earlier in bitransgenic <it>MMTV-Wnt1/MMTV-Neu mice</it>, but no <it>Ras </it>or <it>MMTV-Neu </it>mutations were found in these tumors, which were phenotypically similar to those arising in <it>MMTV-Wnt1 </it>mice. In addition, no <it>Ras </it>mutations were found in the mammary tumors that arise in <it>MMTV-Wnt1 </it>transgenic mice lacking an intact <it>P53 </it>gene.</p> <p>Conclusions</p> <p>Tumorigenic properties of cells undergoing functionally significant secondary mutations in <it>H-Ras </it>or the <it>MMTV-Neu </it>transgene allow selection of those cells in <it>MMTV-Wnt1 </it>and <it>MMTV-Neu </it>transgenic mice, respectively. Alternative sources of oncogenic potential, such as a second transgenic oncogene or deficiency of a tumor suppressor gene, can obviate the selective power of those secondary mutations. These observations are consistent with the notion that somatic evolution of mouse mammary tumors is influenced by the specific nature of the inherited cancer-promoting genotype.</p>http://www.biomedcentral.com/1741-7015/2/24 |
| spellingShingle | Li Yi Podsypanina Katrina Varmus Harold E Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype BMC Medicine |
| title | Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype |
| title_full | Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype |
| title_fullStr | Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype |
| title_full_unstemmed | Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype |
| title_short | Evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype |
| title_sort | evolution of somatic mutations in mammary tumors in transgenic mice is influenced by the inherited genotype |
| url | http://www.biomedcentral.com/1741-7015/2/24 |
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