Context-dependent effects of whole-genome duplication during mammary tumor recurrence
Abstract Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor t...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2021-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-94332-z |
| _version_ | 1818834687695519744 |
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| author | Rachel Newcomb Emily Dean Brock J. McKinney James V. Alvarez |
| author_facet | Rachel Newcomb Emily Dean Brock J. McKinney James V. Alvarez |
| author_sort | Rachel Newcomb |
| collection | DOAJ |
| description | Abstract Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation. |
| first_indexed | 2024-12-19T02:38:47Z |
| format | Article |
| id | doaj.art-697de7b1dc5d4dff8c6dee6e6e68404d |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-19T02:38:47Z |
| publishDate | 2021-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-697de7b1dc5d4dff8c6dee6e6e68404d2022-12-21T20:39:15ZengNature PortfolioScientific Reports2045-23222021-07-0111111710.1038/s41598-021-94332-zContext-dependent effects of whole-genome duplication during mammary tumor recurrenceRachel Newcomb0Emily Dean1Brock J. McKinney2James V. Alvarez3Department of Pharmacology and Cancer Biology, Duke UniversityDepartment of Pharmacology and Cancer Biology, Duke UniversityDepartment of Pharmacology and Cancer Biology, Duke UniversityDepartment of Pharmacology and Cancer Biology, Duke UniversityAbstract Whole-genome duplication (WGD) generates polyploid cells possessing more than two copies of the genome and is among the most common genetic abnormalities in cancer. The frequency of WGD increases in advanced and metastatic tumors, and WGD is associated with poor prognosis in diverse tumor types, suggesting a functional role for polyploidy in tumor progression. Experimental evidence suggests that polyploidy has both tumor-promoting and suppressing effects, but how polyploidy regulates tumor progression remains unclear. Using a genetically engineered mouse model of Her2-driven breast cancer, we explored the prevalence and consequences of whole-genome duplication during tumor growth and recurrence. While primary tumors in this model are invariably diploid, nearly 40% of recurrent tumors undergo WGD. WGD in recurrent tumors was associated with increased chromosomal instability, decreased proliferation and increased survival in stress conditions. The effects of WGD on tumor growth were dependent on tumor stage. Surprisingly, in recurrent tumor cells WGD slowed tumor formation, growth rate and opposed the process of recurrence, while WGD promoted the growth of primary tumors. These findings highlight the importance of identifying conditions that promote the growth of polyploid tumors, including the cooperating genetic mutations that allow cells to overcome the barriers to WGD tumor cell growth and proliferation.https://doi.org/10.1038/s41598-021-94332-z |
| spellingShingle | Rachel Newcomb Emily Dean Brock J. McKinney James V. Alvarez Context-dependent effects of whole-genome duplication during mammary tumor recurrence Scientific Reports |
| title | Context-dependent effects of whole-genome duplication during mammary tumor recurrence |
| title_full | Context-dependent effects of whole-genome duplication during mammary tumor recurrence |
| title_fullStr | Context-dependent effects of whole-genome duplication during mammary tumor recurrence |
| title_full_unstemmed | Context-dependent effects of whole-genome duplication during mammary tumor recurrence |
| title_short | Context-dependent effects of whole-genome duplication during mammary tumor recurrence |
| title_sort | context dependent effects of whole genome duplication during mammary tumor recurrence |
| url | https://doi.org/10.1038/s41598-021-94332-z |
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