Parental metabolic status and offspring cancer risks

描述（由申请人提供）： 该试验性应用旨在确定亲代代谢状态对后代癌症发病的影响。具体来说，我们提出，父母的代谢综合征（MS）增加乳腺癌的发展，在女性后代和前列腺癌的发展，在男性后代。MS的患病率很高，并且随着某些类型的癌症（如乳腺癌和前列腺癌）的发病率增加而增加，这表明MS可能是乳腺癌和前列腺癌的重要病因。流行病学调查和实验研究的累积证据表明，MS的易感性也可能在发育早期通过改变母体饮食摄入量，通过不适当的胎儿或新生儿营养获得。因此，父母，特别是母亲MS可能会在宫内发育期间干扰后代的代谢程序，导致后代MS和随后癌症的风险增加。然而，非常有限的实验研究已经做了调查父母MS和他们的后代癌症风险之间的相互关系。这项试点应用是为了产生关键的实验证据，以检验我们的假设，即父母MS增加女性后代患乳腺癌的风险和男性后代患前列腺癌的风险。我们建议将相关的C3（1）/SV 40 Tag转基因小鼠模型用于所建议的研究。雌性转基因小鼠发生乳腺肿瘤，雄性转基因小鼠发生前列腺肿瘤。具体目标1是确定亲本MS对雌性后代乳腺肿瘤和雄性后代前列腺肿瘤发展的影响。野生型雌性FVB小鼠和雄性C3（1）/SV 40 Tag转基因雄性小鼠将喂食对照饮食或高脂肪/高精制糖（HF/HS）饮食。将分别监测转基因雌性和雄性后代的乳腺肿瘤和前列腺肿瘤的发展。具体目标2是进一步确定与亲本MS对雌性和雄性后代分别发生乳腺癌和前列腺癌的刺激作用相关的相关生物标志物。我们将首先确定一系列的代谢生物标志物在父母和女性和男性后代（目标2A）。此外，将进行cDNA微阵列测定以鉴定潜在的分子靶点，这些分子靶点可能为亲本MS刺激雌性和雄性后代乳腺癌和前列腺癌发展的分子机制提供新的见解（目的2B）。拟定研究将提供直接支持证据，支持或反对亲代MS在雌性后代乳腺癌和/或雄性后代前列腺癌发生中的因果作用。它将提供至关重要的证据，通过减轻父母的代谢紊乱来支持癌症预防策略。这些结果也为未来的RO 1资助申请提供了必要的支持性初步数据，以研究针对父母MS的有效饮食或营养方案预防癌症。

DESCRIPTION (provided by applicant): This pilot application is to determine the effects of parental metabolic status on the onset of cancer in the offspring. Specifically, we propose that parental metabolic syndrome (MS) increases the development of breast cancer in female offspring and the development of prostate cancer in male offspring. The prevalence of MS is high and increasing in parallel with increasing incidences of certain types of cancer, such as breast and prostate cancers, suggesting that MS may be an important etiological factor for breast and prostate cancers. Accumulating evidence from epidemiological investigations and experimental studies has suggested that predisposition to the MS may also be acquired very early in development through inappropriate fetal or neonatal nutrition via altered maternal dietary intake. It is thus possible that parental, especially maternal MS may disturb metabolic programming of the offspring during intrauterine development, resulting in increased risks of MS and subsequent cancer in the offspring. However, very limited experimental research has been done to investigate the inter-relationships between parental MS and cancer risks of their offspring. This pilot application is to generate critical experimental evidence for testing our hypothesis that parental MS increases the risk of breast cancer in female offspring and the risk of prostate cancer in male offspring. We propose to apply a relevant C3(1)/SV40 Tag transgenic mouse model for the proposed studies. Female transgenic mouse develops mammary tumor and male transgenic mouse develops prostate tumor. Specific Aim 1 is to determine the effects of parental MS on the development of mammary tumor in female offspring and prostate tumor in male offspring. The wild-type female FVB mice and male C3(1)/SV40 Tag transgenic male mice will be fed either a control diet or a high fat/high refined sugar (HF/HS) diet. The transgenic female and male offspring will be monitored for the development of mammary tumor and prostate tumor, respectively. Specific Aim 2 is to further determine the related biomarkers that are associated with the stimulatory effect of the parental MS on the development of breast and prostate cancers in the female and male offspring, respectively. We will first determine a series of metabolic biomarkers in the parents and in the female and male offspring (Aim 2A). In addition, cDNA microarray assays will be performed to identify potential molecular targets that may provide new insights into the molecular mechanisms by which the parental MS stimulates the development of breast and prostate cancers in female and male offspring, respectively (Aim 2B). The proposed studies will provide direct supporting evidence to support or against the causal roles of parental MS in the development of breast cancer in female offspring and/or prostate cancer in male offspring. It will provide critically important evidence to support the cancer prevention strategy by alleviating metabolic disorders in the parents. The results also provide essential supporting preliminary data for future RO1 grant application investigate effective dietary or nutritional regimens for cancer prevention by targeting parental MS.