Chemoprevention of pituitary gonadotrope tumors

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DESCRIPTION (provided by applicant): Pituitary adenomas are the most frequent of all pituitary diseases and are observed in both sexes. The prevalence is estimated as ~90 cases per 105 people. The majority arises from the gonadotrope lineage and these tumors do not hypersecrete glycoprotein hormones [i.e., luteinizing hormone (LH) and follicle stimulating hormone (FSH)] and thus are called null cell adenomas. The clinical manifestations include neurological symptoms such as damage to brain tissue and optic chiasm, vision loss, increased intracranial pressure, persistent headache and nausea. Because they have no well-defined diagnostic markers, null cell adenomas often go undetected until they are very advanced and surgery is the only treatment. There are no established model systems or chemoprevention options available for null cell adenomas. We have developed a unique transgenic strain of mice that develops gonadotrope-enriched pituitary adenomas and phenocopies human pituitary null cell adenomas including. Our long-term goal is to understand the mechanisms of origin and progression of null cell adenoma, and develop new strategies of chemoprevention for it. The objective of this proposal is to identify biomarkers and specific targets/pathways responsible for gonadotrope tumor progression such that mechanistic insights into progression and prevention of human null cell adenomas could ultimately be obtained. Our central hypothesis is that both estrogen receptor-1 (ESR1) and Indian hedgehog (IHH) contribute to growth of pituitary gonadotrope adenomas and inhibiting their expression leads to clinical benefit. In Specific Aim 1, we will determine the mechanism by which estrogen signaling influences tumor growth and progression. Effects of estrogen on glycosylation that contribute to hormone secretion failure will be evaluated. Additionally, a novel mouse model in which gonadotrope tumors are fluorescently labeled will be used to identify potential biomarkers. In Specific Aim 2, we will test the efficacyof anti-estrogen therapy to regulate gonadotrope tumor growth. The approach involves the use of mice conditionally overexpressing Esr1 at desired times, and mice lacking either Esr1 or Esr2 on the tumor-prone transgenic background. The in vivo tumor preventive effects of tamoxifen will also be tested. In Specific Aim 3, we will determine the effects of blocking IHH action on gonadotrope tumor development. We will specifically delete Ihh in gonadotrope tumors by using a cre-lox approach. In a second approach, the effects of hedgehog chemoprevention agents will be tested in gonadotrope tumors of transgenic mice. The approach is innovative, because it utilizes a unique transgenic mouse model that develops gonadotrope tumors and uses a combination of in vitro and novel in vivo models. The proposed research is significant because it is expected to vertically advance and expand understanding of how chemopreventive agents targeted to block estrogen and hedgehog signaling regulate gonadotrope/null cell adenomas.