Amplification Studies of MET and Cdk6 in a Rat Endometrial Tumor Model and Their Correlation to Human Type I Endometrial Carcinoma Tumors

Abstract

Cancer is known to be a genetic disease that is both polygenic and heterogeneous, in most cases involving changes in several genes in a stepwise fashion. The spectrum of individual genes involved in the initiation and progression of cancer is greatly influenced by genetic factors unique to each patient. A study of complex diseases such as cancer is complicated by the genetic heterogeneous background and environmental factors in the human population. Endometrial cancer (EC) is ranked fourth among invasive tumors in women. In Sweden, approximately 1300 women (27/100,000 women) are diagnosed annually. To be able to study the genetic alterations in cancer, the use of an animal model is very convenient. Females of the BDII strain are genetically predisposed to EC and 90% of female BDII rats develop EC during their lifetime. Thus, BDII rats have been used to model human EC with respect to the genetics of susceptibility and of tumor development. A set of rat EC tumors was analyzed using conventional cytogenetics and comparative genome hybridization (CGH). Chromosomal aberrations, i.e., gains, were found on rat chromosome 4 (RNO4). Using FISH analysis, we concluded that the Met oncogene and Cdk6 (cyclin-dependent kinase 6) were amplified in this set of EC tumors. The data from this investigation were used to analyze a set of human endometrial tumors for amplification of Cdk6 and Met. Our preliminary data are indicative for a good correlation between our findings in the BDII rat model for EAC and the situation in human EC. These data provide strong support for the use of animal model systems for better understanding and scrutinizing of human complex disease of cancer.

TET1 is a Tumor Suppressor That Inhibits Papillary Thyroid Carcinoma Cell Migration and Invasion

“…e present study also found that the expression of protooncogenes CDK6, MCF2L, and EDN1 was upregulated along with WNT4 and FZD4. e expression of CDK6, as a protooncogene, was upregulated in numerous tumors [34,35]. e overexpression of the MCF2L gene, encoding guanosine conversion factor, could activate the key regulatory factors of the Rho GTP family (Cdc42 and Rac1) and promote tumor metastasis in breast cancer cells [36].…”

BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors

“…Since RNO10, 12 and 20 displayed the most recurrent alterations (over 20%) in the M-CGH analysis we chose an average distance between BAC clones of 0.46 to 0.92 Mb for these three chromosomes on the array. High resolution BAC clone coverage was also prepared for chromosome 4, 5 and 6, as earlier studies in our group repeatedly pinpointed to potential significance of aberrations in these chromosomes in tumor development [ 22 , 23 , 27 ]. For the rest of the chromosomes, BAC clone coverage was less dense with an average distance of 3 Mb.…”

Modeling Endometrial Cancer: Past, Present, and Future

“…Another piece of evidence is that melengestrol acetate administration suppresses tumor growth [85]. Tumors from BDII/Han rats have been extensively genomically characterized, and the results suggest that the upregulation of CDK6 and/or Met could play a role in the development of cancerous lesions [86,87,88,89,90,91,92,93,94]. …”