Role of p53 polymorphisms in disparities in breast carcinogenesis and outcome .

p53 多态性在乳腺癌发生和结果差异中的作用。

• 批准号: 8494814
• 负责人: ROBIN S FUCHS-YOUNG
• 金额: $ 29.28万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-13 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8494814
• 关键词: Address; African American; Alleles; Animal Model; Apoptosis; Apoptotic; Arginine; Biological; Body Weight; Breast; Breast Cancer Model; Cancer Patient; Caucasians; Caucasoid Race; Codon Nucleotides; Collaborations; Databases; Development; Disease; ERBB2 gene; Economic Factors; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Epithelium; Equilibrium; Exons; Frequencies; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genotype; Goals; Growth Factor; Health; Hormonal; Human; Human Genetics; In Vitro; Incidence; Indium; Individual; Insulin-Like Growth Factor I; Light; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediator of activation protein; Melissa; Minority; Modeling; Molecular; Molecular Target; Multiparity; Mutation; Oncogenic; Outcome; Pathway interactions; Phenotype; Population; Positioning Attribute; Postmenopause; Predisposition; Pregnancy; Premenopause; Prevention strategy; Proline; Protein p53; Public Health; Risk; Risk Factors; Role; Sampling; TP53 gene; Testing; Tumor Bank; Variant; Woman; base; cancer health disparity; carcinogenesis; early onset; energy balance; genetic analysis; health disparity; homologous recombination; improved; in vitro Model; in vivo; inhibitor/antagonist; malignant breast neoplasm; mouse model; novel; outcome forecast; overexpression; parity; research study; response; social; treatment strategy; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Minority women, specifically African Americans (AAs), are substantially more likely than Caucasians to develop early onset breast cancer (EOBC) that is frequently aggressive and has a poor prognosis. In addition, epidemiologic studies have shown that AA women do not enjoy the same protection conferred by early full- pregnancy and multiparity as do Caucasian women. Some of these studies show that the risks of pre- menopausal breast cancer and more aggressive forms of the disease are actually increased by parity and early pregnancy in AA women. The molecular basis for this racial disparity is not known, but it is likely that the highly proliferative state achieved during development of the lactational differentiation, without appropriate homeostatic balance produced by subsequent waves of apoptosis, could contribute to this increased risk. We hypothesize that racially disproportionate p53 variants with reduced or altered function contribute to breast cancer health disparities and lack of pregnancy protection in AA women. In particular we propose that a non-synonymous SNP that results in either a proline (P) or arginine (R) at position 72 of the p53 protein may be an important contributor to this health disparity. The frequency of the P allele, which has been shown to be a less potent inhibitor of oncogenic transformation in vitro and to have reduced capacity to induce apoptosis in vivo, is much higher (66.6%) in AA than in Caucasian women (23.3%). We will test this hypothesis using the one existing animal model that harbors a "humanized" p53 gene, obtained by targeted homologous recombination of exon 4, encoding either R or P at codon 72. In specific aim 1, we will use this animal model to investigate whether the P allele, which is more frequent in AA women, provides a reduced level of pregnancy- induced mammary cancer protection than the R allele, which is more prevalent in Caucasian women. In specific aim 2, using the same animal model, we will investigate if the P allele cooperates with HER-2 in development of aggressive, early onset disease. Overexpression of Her-2 is one of the most common genetic alterations found in tumors from young AA breast cancer patients. In specific aim 3, we will investigate if the p53 alleles interact with the IGF-1 pathway. IGF-1 is an important mediator of the effects of energy balance and is another putative target of molecular alteration during mammary tumorigenesis. Finally, in Aim 4 we will investigate whether our mechanistic findings in animal models can be substantiated in human samples obtained from AA breast cancer patients. It is anticipated that these novel studies will shed new light on the molecular basis for outcome disparities in breast cancer, particularly the interactions of biological risk factors that may contribute to development of aggressive, early onset disease. Since a better understanding of the mechanisms involved in breast carcinogenesis in minority populations carries the promise of improved prevention and treatment strategies, this project directly and innovatively addresses the goal of reducing and/or eliminating health disparities.

描述(由申请人提供)：少数族裔女性，特别是非裔美国人(AA)，比高加索人更有可能患上早发性乳腺癌(EOBC)，这种癌症往往具有侵袭性，预后差。此外，流行病学研究表明，再生障碍性贫血妇女没有享受到与高加索妇女一样的早期完全怀孕和多胎所提供的保护。其中一些研究表明，在AA妇女中，生育和早孕实际上增加了绝经前乳腺癌和更具侵袭性的疾病的风险。这种种族差异的分子基础尚不清楚，但很可能是在乳汁分化发展过程中达到的高度增殖状态，如果没有随后的凋亡浪潮所产生的适当的动态平衡，可能会导致这种风险的增加。我们假设，在AA妇女中，功能降低或改变的P53变异在种族上不成比例地导致乳腺癌、健康差异和缺乏妊娠保护。特别是，我们提出，导致P53蛋白第72位的脯氨酸(P)或精氨酸(R)的非同义SNP可能是造成这种健康差异的重要因素。P等位基因在体外对致癌转化的抑制作用较弱，在体内诱导细胞凋亡的能力减弱，在再障患者中的频率(66.6%)远远高于高加索女性(23.3%)。我们将使用一个现有的动物模型来验证这一假设，该模型包含一个通过外显子4的定向同源重组获得的人源化的p53基因，该外显子在密码子72编码R或P。在具体目标1中，我们将使用这个动物模型来研究在AA女性中更常见的P等位基因是否比在高加索女性中更常见的R等位基因提供的妊娠诱导乳腺癌保护水平更低。在特定的目标2中，使用相同的动物模型，我们将调查P等位基因是否与HER-2在侵袭性早发性疾病的发生中协同作用。HER-2的过度表达是年轻AA乳腺癌患者肿瘤中最常见的基因改变之一。在特定的目标3中，我们将研究P53等位基因是否与IGF-1途径相互作用。IGF-1是能量平衡效应的重要介体，也是乳腺肿瘤发生过程中分子改变的另一个可能靶点。最后，在目标4中，我们将研究我们在动物模型中的机制发现是否可以在AA乳腺癌患者的人类样本中得到证实。预计这些新的研究将为乳腺癌预后差异的分子基础提供新的线索，特别是可能导致侵袭性早发性疾病发展的生物危险因素的相互作用。由于更好地了解少数群体乳腺癌发生的机制有助于改进预防和治疗战略，该项目直接和创新性地解决了减少和/或消除健康差距的目标。