Telomere dysfunction suppresses multiple endocrine neoplasia in mice
Ji-Hyeon Lee1, Miriam Anver2, Maria Kost-Alimova3,4, Alexei Protopopov3,4, Ronald A. DePinho3,5 and Sushil G. Rane1
1 Diabetes, Endocrinology & Obesity Branch, National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD
2 Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD
3 Dana-Farber Cancer Institute, Boston, MA
4 Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX
5 Department of Cell Biology, University of Texas MD Anderson Cancer Center, Houston, TX
Correspondence:
Sushil G. Rane, email:
Keywords: Telomerase, Pituitary, Pancreas, Islets, Endocrine Neoplasia
Received: July 31, 2014 Accepted: September 5, 2014 Published: September 5, 2014
Abstract
Multiple endocrine neoplasia (MEN) syndrome is typified by the occurrence of tumors in two or more hormonal tissues. Whereas the genetics of MEN syndrome is relatively well understood, the tumorigenic mechanisms for these cancers remain relatively obscure. The Cdk4R24C mouse model develops highly penetrant pituitary tumors and endocrine pancreas adenomas, and, as such, this model is appropriate to gain insight into mechanisms underlying MEN. Using this model, here we provide evidence supporting an important role for telomerase in the pathogenesis of MEN. We observed increased aneuploidy in Cdk4R/R fibroblasts along with significantly elevated telomerase activity and telomere length in Cdk4R/R islets and embryonic fibroblasts. To better understand the role of telomerase, we generated Cdk4R24C mice with inactivation of the mTERC locus, which codes for the essential RNA component of the enzyme telomerase (mTERC-/- Cdk4R/R mice). Embryonic fibroblasts and islets derived from mTERC-/- Cdk4R/R mice exhibit reduced telomere length and proliferative capacity. Further, mTERC-/- Cdk4R/R fibroblasts display reduced transformation potential. Importantly, mTERC-/- Cdk4R/R mice display significantly reduced spontaneous tumorigenesis. Strikingly, we observed dramatic suppression of pituitary tumors and endocrine pancreas adenomas in mTERC-/- Cdk4R/R mice. Telomere dysfunction suppressed tumor initiation and increased latency of tumor development while not affecting the progression of established tumors. In summary, these results are suggestive of an important role for telomerase in tumor development in the Cdk4R24C mouse model, specifically in the genesis of tumors in the pituitary and the endocrine pancreas.
