PTTG driven tumorigenesis

In females, ovarian cancer is among the most fatal malignancies encountered. Described as the silent killer, ovarian epithelial cancer has no identifiable precancerous lesions that an be used for screening purposes. The primary reason for this outcome is the lack of an appropriate animal model that can be used to study disease progression. Ovarian epithelial cancer arises because of a high degree of genetic damage at both the chromosomal and molecular level. With many oncogenes implicated in ovarian tumorigenesis, a recently identified oncogene known as Pituitary Tumor Transforming Gene (PTTG) also known as securin, was found to be over-expressed in different types of ovarian cancers, including ovarian epithelial cancer.; PTTG is a 202 amino acid protein that shares no significant homology with any other protein identified to date. PTTG functions as an inhibitor of sister chromatid separation through-out the cell cycle. Over-expression of PTTG was found to induce aneuploidy, genomic instability, invasiveness and metastasis; all of which are mechanisms that contribute to cellular transformation.; To elucidate the role of PTTG in ovarian epithelial cancer, we developed a transgenic mouse model that utilized the MISIIR promoter to target PTTG to the ovarian surface epithelium as well as to granulosa cells. MISIIR-PTTG transgenic females developed an increased corpus luteum mass and increased cystic glandular hyperplasia of the endometrium. Furthermore, both serum LH and testosterone levels were elevated in transgenic female compared to wild type females. Therefore, we conclude that PTTG is capable of changing the cellular environment, and likely requires the activation of a second oncogene to achieve cellular transformation.; To test if the suppression of PTTG in ovarian cancer cells may provide a therapeutic advantage in ovarian cancer treatment, we utilized small inhibitory RNA (siRNA) to silence PTTG expression in human A2780 ovarian carcinoma cells and assessed the effect of PTTG silencing on tumor formation in vitro and in vivo. Our data indicate that decreased expression of PTTG modulates anchorage-dependent and independent growth of A2780 cells. Furthermore, decreased levels of PTTG protein reduce both tumor incidence and tumor growth in nude mice.