Alcoholism is known to induce hyperprolactinomas, a condition when the plasma level of prolactin is elevated, in both men and women. Hyperprolactinemia, is known to be one of the major reasons for reproductive dysfunction such as amenorrhea, galactorrhea and infertility in human. Many of the patients with hyperprolactinemia also show prolactin-secreting pituitary adenomas (prolactinomas). Pituitary tumors represent 10?15% of intra-cranial tumors. While most are benign and can be controlled by current therapeutics, some show a lack of sensitivity to a combination of therapies or recur during follow-up and are considered as aggressive with unclear epidemiology. About 0.2% of pituitary tumors are associated with distant metastasis (most frequently in central nervous system, liver and bones) and with a mean survival of between 1 and 3 years. A significant number of reports now identified alcoholism as a potential contributor to the development of aggressive tumors in various tissues including pituitary gland. Although the mechanism by which alcohol promotes aggressiveness of tumors is not known, increasing evidence suggests that aberrant patterns of DNA methylation, an important epigenetic mechanism of transcriptional control, could be part of the pathogenetic mechanisms that lead to the development of alcohol-induced aggressive tumors. Using animal model of prenatal alcohol exposures, which maintains stable alcohol epigenetic marks on the genome, we identified epigenetic modifications of key regulatory genes that enhances cell stemness in the pituitary. In this proposal, we test the role of a novel stem cell regulatory developmental pluripotency associated-4 (DPPA44) gene in mediation of alcohol effects on the development of aggressive tumor in the pituitary. We hypothesize that alcohol epigenetically modifies the promoter region of DPPA4 gene to enhance oncogenic properties of this transcription factor in the pituitary under the estrogenic influence that promote the development of aggressive prolactinomas in prenatal alcohol exposed rats. To test these hypotheses we will employ pituitary tumor stem cell spheres (pituispheres) to determine if prenatal alcohol exposure enhances the oncogenic potential of DPPA4 in the pituitary. We will evaluate the potential mechanism contributing to oncogenic transformation by DPPA4. We will conduct experiments to elucidate the mechanism by which prenatal alcohol exposure epigenetically modifies the DPPA4 gene to increase its oncogenic property. We will study the interaction between DPPA4 and dopamine D2 receptor in the promotion of aggressive pituitary tumors and access the role of interaction between DPPA4 and estrogen receptor1 in the promotion of aggressive pituitary tumors. We will employ various cellular and molecular approaches, gene editing techniques and genome wide expression analysis to investigate molecular actions of DPPA4 in mediation of alcohol effects on pituitary tumor cell growth and progression.Together these studies should establish how alcohol epigenetically programs the pituitary to overexpress DPPA4 gene and how this transcription factor interacts with dopamine D2 receptor and estrogen receptor to control the development of aggressive prolactinomas. The information gained from the proposed studies should lead to development of DPPA4 and dopamine D2 receptor based therapy to control aggressive tumors in the pituitary.
The main goal of this proposal is to use rat pituitary tumor progenitor cell model to test the hypotheses if prenatal alcohol exposure enhances the oncogenic potential of DPPA4 by interacting with dopamine D2 receptor and estrogen receptor 1 in the pituitary. The findings of these experiments will form a novel treatment strategy targeting DPPA4 for better prognosis and treatment outcome of aggressive pituitary tumors.
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