Human breast cancer arises through the acquisition of genetic changes that endow precursor cancer cells with a critical threshold of cancer-relevant genetic lesions. This complex genomic alterations confer upon precursor cancer cells the ability to grow indefinitely and to metastasize to distant sites. One important mechanism underlying a cell's tumorigenic potential is the status of its telomere. Telomeres are G-rich simple repeat sequences that serve to prevent chromosomal ends from being recognized as DMA double- strand breaks (DSBs). Dysfunctional telomeres resemble DSBs, leading to the formation of dicentric chromosomes that fuel high degrees of genomic instability. In the setting of an intact p53- dependent DNA damage response (DDR) pathway, this instability promotes cellular senescence, a potent tumor suppressor mechanism. However, rare cells that stochastically lose p53 function progress towards cancer. In human breast carcinomas, the observation that telomere dysfunction is associated with the transition from benign ductal hyperplasia to malignant DCIS strongly supports the notion that dysfunctional telomere-driven genomic instability initiates the development of breast cancer. In this proposal, we aim to generate mouse models that faithfully recapitulate human telomere biology in vivo. The telomere binding protein POT1 (protection of telomeres 1) is a single-stranded telomere binding protein that is essential for chromosomal end protection. We recently generated a Pot1 conditional knockout mouse, and show that deletion of Pot1 induces a potent DNA damage response at telomeres that triggers a senescence phenotype in the absence of p53. Deletion of Pot1 also results in extensive chromosomal fusions and progression to cancer in the setting of p53 deficiency. In this proposal we will develop mouse models to examine the role of telomere dysfunction in the pathogenesis of mammary carcinoma in the settings of p53 competence or deficiency and characterize chromosomal aberrations in mouse breast tumor samples. We will also investigate the function of Pot1 loss in human breast cancers. Our proposal should provide mechanistic insights into how the DDR pathway senses dysfunctional telomeres to promote senescence in vivo. The finding that senescence inhibits breast cancer formation could have therapeutic implications. It is likely that up regulation of p53 function by compounds currently undergoing clinical trials would favor the activation of the cellular senescence program, resulting in suppression of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129037-05
Application #
8145661
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Pelroy, Richard
Project Start
2007-08-08
Project End
2013-04-30
Budget Start
2011-08-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2011
Total Cost
$305,017
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gu, P; Wang, Y; Bisht, K K et al. (2017) Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis. Oncogene 36:1939-1951
Hu, Chunyi; Rai, Rekha; Huang, Chenhui et al. (2017) Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. Cell Res 27:1485-1502
Chen, Cong; Gu, Peili; Wu, Jian et al. (2017) Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nat Commun 8:14929
Rai, Rekha; Chen, Yong; Lei, Ming et al. (2016) TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun 7:10881
Wang, Yang; Wang, Xinwei; Flores, Elsa R et al. (2016) Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell 15:646-60
Lee, Youngsoo; Brown, Eric J; Chang, Sandy et al. (2014) Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss. J Neurosci 34:7836-44
Gupta, Romi; Dong, Yuying; Solomon, Peter D et al. (2014) Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A. Proc Natl Acad Sci U S A 111:E3062-71
Chang, Sandy (2013) Cancer chromosomes going to POT1. Nat Genet 45:473-5
Wang, Yang; Sharpless, Norman; Chang, Sandy (2013) p16(INK4a) protects against dysfunctional telomere-induced ATR-dependent DNA damage responses. J Clin Invest 123:4489-501
Wan, Bingbing; Yin, Jinhu; Horvath, Kent et al. (2013) SLX4 assembles a telomere maintenance toolkit by bridging multiple endonucleases with telomeres. Cell Rep 4:861-9

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