RT Journal Article
SR Electronic
T1 Context-dependent effects of whole-genome duplication during mammary tumor recurrence
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.05.03.442527
DO 10.1101/2021.05.03.442527
A1 Rachel Newcomb
A1 Emily Dean
A1 James V. Alvarez
YR 2021
UL http://biorxiv.org/content/early/2021/05/04/2021.05.03.442527.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.