Cell survival and cell death regulation in gynecological cancers.
BACKGROUND & RATIONALE
Endometrial cancer (EC) is the leading type of female genital cancer in the Western world and ranks fourth among the most common cancers in women. Patients with tumour confined to the uterus are treated with surgery and radiotherapy; however, more than 25% of patients diagnosed with endometrial carcinoma have an invasive primary tumour accompanied by regional and/or distant metastases. Ovarian cancer (OC) is the fifth most common cancer in women and is the leading cause of death among the female genital tract malignancies. The 5-year survival rate of these women is only 20?30%. The balance between survival and apoptotic factors is crucial in determining tumour cell fate (growth vs cell death), especially during chemotherapy and metastasis. Survival and apoptosis are both regulated at the intracellular level and through extra-cellular hormones. However, how these factors interact to regulate chemoresistance and metastasis is unknown and how they act specifically in these hormone-dependent cancers is not well established. Thus, chemoresistance and metastasis represent the major causes of treatment failure. The process of chemoresistance, tumor growth and progression is linked primarily to the malfunction of apoptotic pathways. Deletion and mutation of tumor suppressor genes are two of the several events underlying the loss of apoptotic pathway. However, such deleted or mutated genes cannot be recruited in therapeutic strategies owing to their permanent loss of function. Therefore, the identification of pro-apoptotic tumor suppressor genes that are functionally silenced rather than mutated or deleted, offers the prospect of reactivating them functionally as a strategy for cancer treatment. One promising candidate gene is prostate apoptosis response-4 (Par-4). We have recently demonstrated that Par-4 is a direct target of caspase-3 during apoptosis induction and that the resulting cleaved fragment can be responsible for this effect through its translocation to the nucleus. However, how this fragment is regulated and what are its mechanisms of action is unknown. We have evidenced that Par-4 can be downregulated by estrogens.
OVERALL OBJECTIVE AND HYPOTHESIS: The overall objective of the proposed research program is to examine the role of Par-4 in OC and EC progression and how it regulates apoptosis induction in response to chemotherapeutic drugs. The hypotheses for the proposed research project is that Inhibition of Par-4 expression by 17b-estradiol could increase the apoptotic response and chemosensitivity of OC and EC cells.
SPECIFIC OBJECTIVES: To determine the role of 17b-estradiol in the regulation of Par-4 during cancer cell survival.
INNOVATION & SIGNIFICANCE: These studies should establish the contribution of Par-4 in the processes of OC and EC chemoresistance and invasion/metastasis. Ultimately, this should allow us to propose multiple new avenues that could be envisaged for the treatment of chemoresistant and metastatic cancers, the primary cause of cancer death. This comprehensive program will set the basis and provide crucial clues in understanding the mechanisms of chemoresistance and tumor metastasis.
