Ovarian cancer is the most lethal gynaecological malignancy and is the sixth most common cause of cancer- related death for Australian women. Aging increases the risk of the disease development with majority of ovarian cancers diagnosed in post-menopausal women. Approximately 90% of all ovarian cancers are suspected to arise from ovarian surface epithelium (OSE) or the epithelium of the fallopian tube. The repeated process of ovulation, rupture and repair, combined with exposure to growth promoting factors of the follicular fluid, is known to create an abnormal environment for uncontrolled proliferation of the epithelium of both the ovary and fallopian tube leading to ovarian cancer. Overactive mTOR signalling is associated with aging and cancer. We have previously established that hyperactivation of the mTOR pathway is a frequent event in ovarian cancer and is associated with a worse prognosis for these patients. We hypothesised that consituitive activation of mTOR signalling in aged ovaries causes uncontrolled proliferation of epithelial cells leading to cancer.
Histological examination of the ovaries of the aged mice (18 months) revealed OSE cell hyperplasia and abnormal papillary growth. To understand if overactive mTOR signalling is responsible for these pathological changes, 9-month old mice (N=28) were treated with three different doses of rapamycin, an mTOR inhibitor, for 12 months. We observed significant reduction in OSE hyperplasia in mice treated with rapamycin compared to controls. Examination of ovaries from Pten heterozygous and Pten transgenic mice further confirmed that mTOR overactivation leads to age dependent OSE hyperplasia. In human ovarian cancer cells, suppression of mTOR signaling using the FDA approved mTOR inhibitors (Everolimus and NVPBEZ235) reduced cell viability, proliferation and colony forming ability. Collectively, we have shown that hyperactivation of the mTOR pathway is an early event in ovarian carcinogenesis.