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: 8241660
• 负责人: ROBIN S FUCHS-YOUNG
• 金额: $ 7.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN 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 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241660
• 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; public health relevance; 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. PUBLIC HEALTH RELEVANCE: The proposed project will investigate genetic contributors to the development of aggressive, early onset breast cancer in minority women. We hypothesize that the increased likelihood that minority, particularly AA, women will develop pre- versus post- menopausal disease is a critical contributor to breast cancer health disparities. As the improved understanding of the causes of early onset breast cancer carries with it the promise of more efficacious treatment and prevention strategies, this proposal directly addresses the important public health 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)，比白种人更容易患早发性乳腺癌 (EOBC)，这种乳腺癌通常具有侵袭性且预后不良。此外，流行病学研究表明，AA 女性无法享受与白人女性相同的早期满孕和多产所带来的保护。其中一些研究表明，绝经前乳腺癌和更具侵袭性的乳腺癌的风险实际上会因 AA 女性生育和早孕而增加。这种种族差异的分子基础尚不清楚，但很可能是在泌乳分化发育过程中实现的高度增殖状态，而没有随后的细胞凋亡浪潮产生适当的稳态平衡，可能导致这种风险增加。 我们假设，功能降低或改变的种族不成比例的 p53 变异会导致 AA 女性乳腺癌健康差异和缺乏妊娠保护。我们特别提出，在 p53 蛋白 72 位产生脯氨酸 (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 等位基因在体外被证明是一种不太有效的致癌转化抑制剂，并且在体内诱导细胞凋亡的能力降低，AA 中的 P 等位基因的频率 (66.6%) 远高于白人女性 (23.3%)。我们将使用一个现有的动物模型来测试这一假设，该动物模型含有“人源化”p53基因，该基因是通过外显子4的靶向同源重组获得的，在密码子72处编码R或P。在具体目标1中，我们将使用该动物模型来研究P等位基因（在AA女性中更常见）是否比R等位基因（在AA女性中更常见）提供较低水平的妊娠诱发乳腺癌保护作用。 白人女性。在具体目标 2 中，我们将使用相同的动物模型来研究 P 等位基因是否与 HER-2 协同作用来发展侵袭性早发性疾病。 Her-2 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。在具体目标 3 中，我们将研究 p53 等位基因是否与 IGF-1 通路相互作用。 IGF-1 是能量平衡效应的重要介质，也是乳腺肿瘤发生过程中分子改变的另一个假定靶点。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从 AA 乳腺癌患者获得的人类样本中得到证实。 预计这些新研究将为乳腺癌结果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疾病发展的生物风险因素的相互作用。由于更好地了解少数群体乳腺癌发生机制有望改善预防和治疗策略，因此该项目直接且创新地实现了减少和/或消除健康差异的目标。 公共卫生相关性：拟议项目将调查少数族裔女性罹患侵袭性早发性乳腺癌的遗传因素。我们假设，少数族裔（尤其是 AA 族）女性在绝经前与绝经后罹患疾病的可能性增加是造成乳腺癌健康差异的一个关键因素。由于对早发性乳腺癌病因的进一步了解有望带来更有效的治疗和预防策略，因此该提案直接解决了减少和/或消除健康差异的重要公共卫生目标。