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

描述（由申请人提供）：少数族裔女性，特别是非洲裔美国人（AAs），比白种人更有可能患上早期乳腺癌（EOBC），这种癌症通常具有侵袭性，预后差。此外，流行病学研究表明，白人妇女不能像白人妇女那样享受到早期妊娠和多胎所带来的同样的保护。其中一些研究表明，AA妇女的产次和早孕实际上增加了绝经前乳腺癌和更严重形式的疾病的风险。这种种族差异的分子基础尚不清楚，但很可能是在哺乳期分化发展过程中达到的高度增殖状态，而随后的细胞凋亡浪潮没有产生适当的稳态平衡，可能导致这种风险增加。我们假设，种族比例失调的p53变异与功能降低或改变导致了AA女性的乳腺癌健康差异和缺乏妊娠保护。我们特别提出，在p53蛋白的第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等位基因的频率（66.6%）远高于高加索女性（23.3%），而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也较弱。我们将使用一个现有的动物模型来验证这一假设，该模型含有“人源化”p53基因，该基因是通过对编码密码子72 R或P的外显子4的靶向同源重组获得的。在具体的目的1中，我们将使用该动物模型来研究在AA女性中更常见的P等位基因是否比在高加索女性中更普遍的R等位基因提供更低水平的妊娠性乳腺癌保护。在特定目标2中，使用相同的动物模型，我们将研究P等位基因是否与HER-2在侵袭性早发性疾病的发展中起作用。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。在具体目标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是能量平衡影响的重要介质，也是乳腺肿瘤发生过程中分子改变的另一个被认为的靶点。最后，在Aim 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。预计这些新的研究将揭示乳腺癌预后差异的分子基础，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民族人群中乳腺癌发生的机制有望改善预防和治疗战略，因此该项目直接和创新地解决了减少和/或消除健康差距的目标。

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.