DOES PKU PROTECT AGAINST CANCER?

描述(申请人提供)：苯丙酮尿症(PKU) 由苯丙氨酸羟化酶(PAH)编码基因突变引起 这会导致高苯丙氨酸血症和异常水平升高 苯丙氨酸代谢物。这些代谢物中有苯乙酸，或 苯乙酸酯(PA)分子的电离形式。最近，PA来了 由于其显示的抗癌活性，正在进行密集的调查 抗多种恶性肿瘤，包括乳腺癌和前列腺癌。 这些发现表明，北大可能会提供保护，防止 由于血液中PA水平的长期升高而导致癌症。调查员的 总体目标是检验这一假设。这将通过以下方式实现 涉及两个活体小鼠模型的研究。特定目标1将评估 使用PA类似物抑制治疗干预的能力 利用研究者现有的芳香化酶进行雌激素依赖的致癌作用 转基因小鼠群体。在这些实验中，PA衍生物4-氯-PA 将长期给小鼠饮用饮用水和它的 化学预防作用在癌前病变/肿瘤发生中的作用 损伤评估。《特定目标2》将检验北京大学能够 用“PKU小鼠”预防乳腺癌。这些研究将利用 建立了PKU小鼠模型(ENU2/2)，该模型的基因编码存在突变 用于多环芳烃，并显示一系列可与 受影响的人类个体。ENU2/2小鼠将接受治疗 化学致癌物DMBA在不同方案下的诱导作用 与相同遗传背景的对照小鼠相比，乳腺肿瘤的发生率更高。 总而言之，从这些活体研究中获得的信息将 确定导致PKU的遗传疾病是否可以预防 乳腺癌的病因可能涉及激素和/或环境因素 (致癌物质)。

DESCRIPTION (provided by applicant): The disease phenylketonuria (PKU) is caused by mutations in the gene coding for phenylalanine hydroxylase (PAH) which results in hyperphenylalaninemia and elevated levels of abnormal phenylalanine metabolites. Among these metabolites is phenylacetic acid, or the ionized form of the molecule phenylacetate (PA). Recently, PA has come under intense investigation due to its demonstrated anticancer activity against a variety of malignancies, including breast and prostate cancers. These findings suggest the possibility that PKU may offer protection against cancer through chronically elevated blood levels of PA. The investigator's overall objective is to test this hypothesis. This will be accomplished by studies involving two in vivo mouse models. Specific Aim 1 will assess the ability of therapeutic intervention with a PA analogue to inhibit estrogen-dependent carcinogenesis using the investigator's existing aromatase transgenic mouse colony. In these experiments, the PA derivative 4-chloro-PA will be chronically administered to the mice in their drinking water and its chemopreventative activity on the development of preneoplastic / neoplastic lesions assessed. Specific Aim 2 will test the hypothesis that PKU can protect against breast cancer using "PKU mice". These studies will utilize an established PKU mouse model (ENU2/2), which has a mutation in the gene coding for PAH and display a range of phenotypic characteristics comparable to those of affected human individuals. The ENU2/2 mice will be treated with the chemical carcinogen DMBA under different protocols and the resulting induction of mammary tumors compared with control mice of the same genetic background. Taken together, the information gained from these in vivo studies will determine whether the genetic disorder that results in PKU can protect against breast cancer whose etiology may involve hormonal and/or environmental factors (carcinogens).