Biology of Race and Progression Associated Breast Tumor Gene Expression

种族和进展相关乳腺肿瘤基因表达的生物学

• 批准号: 8687036
• 负责人: CHARLES M. PEROU
• 金额: $ 31.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687036
• 关键词: Address; African American; Agar; Age; Biological; Biology; Breast; Breast Cancer Cell; Breast Cancer Model; Cancer Prognosis; Cancer cell line; Case-Control Studies; Cell Line; Clinical; Data; Epidemiology; Gene Expression; Gene Expression Profile; Gene Proteins; Genes; Genetic Polymorphism; Growth; High Prevalence; Histologic; Immunofluorescence Immunologic; Incidence; Link; MCF10A cells; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Molecular; Morphogenesis; Morphology; Normal Cell; Normal tissue morphology; Onset of illness; Outcome; Pathway interactions; Patients; Phenotype; Population; RNA Sequences; Race; Reproductive History; Sequence Analysis; Sequence Determination; Series; Tissue Sample; Tumor Subtype; Tumor Tissue; Tumorigenicity; Woman; Women' s Group; Work; cancer cell; cancer health disparity; cell type; genetic variant; in vitro Assay; in vivo; malignant breast neoplasm; mortality; outcome forecast; overexpression; population based; public health relevance; racial difference; research study; triple-negative invasive breast carcinoma; tumor; tumor progression; young woman

DESCRIPTION (provided by applicant): Among young women (<40), breast cancer incidence is higher among black women than white women, but at older ages, incidence is higher among white women than black women. The 'black-white crossover' in incidence has been interpreted as evidence of intrinsic biological differences in young, black women's breast cancer. In support of intrinsic biological differences in black vs. white tumors, our work in the Carolina Breast Cancer Study (CBCS), a large population-based case-control study that oversamples young African American (AA) women, demonstrated that young black women are more likely to get basal-like breast cancer (a poor prognosis cancer) and less likely to develop luminal breast cancer (the cancer with the best prognosis). However, we hypothesize that beyond intrinsic subtype (and within basal-like and luminal subtypes), there are additional biological differences in black vs. white tumors that arise due to ancestral differences in expression of genes involved in breast cancer progression. To understand the contribution of ancestry and race-related markers to cancer progression, it is important to (1) study expression and gene sequence differences in both tumor tissue and normal tissue, and (2) to identify the mechanistic implications of these expression differences in breast cancer and normal cells. Aim 1 of this project will perform expression and gene sequence studies of tumor tissues to identify race-related changes that are also associated with cancer progression, while in Aim 2 the expression and gene sequence of normal tissue will be used to evaluate whether these progression-related genes differ prior to disease onset. These first two aims will use both tumor and normal tissues from two well characterized populations (Carolina Breast Cancer Study and the Normal Breast Study) with substantial proportions of African American patients. These biospecimens will be used to perform RNA-sequencing for quantitative gene expression, and gene sequence analysis, to identify race-associated gene expression differences and polymorphisms that contribute to cancer progression and mortality disparities. Having identified key expression and sequence differences, in Aim 3 will study these genes and their pathways in breast cell lines to evaluate their effects on normal morphogenesis and on cancer progression. The data from this project will identify new biological targets in race-associated breast cancer mortality and will identify the mechanisms by which race-associated gene expression differences promote tumor progression among African American women.

描述（由申请人提供）：在年轻女性（<40岁）中，黑人女性的乳腺癌发病率高于白色女性，但在老年，白色女性的发病率高于黑人女性。发病率的“黑白交叉”被解释为年轻黑人女性乳腺癌内在生物学差异的证据。为了支持黑人与白色肿瘤的内在生物学差异，我们在卡罗莱纳乳腺癌研究（CBCS）中的工作，这是一项大型基于人群的病例对照研究，对年轻的非洲裔美国人（AA）女性进行了过度采样，表明年轻的黑人女性更有可能患基底样乳腺癌（一种预后不良的癌症），而不太可能患管腔型乳腺癌（预后最好的癌症）。然而，我们假设除了内在亚型（以及基底样和管腔亚型）之外，由于乳腺癌进展中涉及的基因表达的祖先差异，黑色与白色肿瘤中存在额外的生物学差异。为了了解血统和种族相关标志物对癌症进展的贡献，重要的是（1）研究肿瘤组织和正常组织中的表达和基因序列差异，以及（2）确定乳腺癌和正常细胞中这些表达差异的机制意义。该项目的目标1将进行肿瘤组织的表达和基因序列研究，以确定与癌症进展相关的种族相关变化，而在目标2中，正常组织的表达和基因序列将用于评估这些进展相关基因在疾病发作前是否不同。前两个目标将使用来自两个充分表征的人群（卡罗莱纳乳腺癌研究和正常乳腺研究）的肿瘤和正常组织，其中非洲裔美国人患者占很大比例。这些生物标本将用于进行定量基因表达的RNA测序和基因序列分析，以确定导致癌症进展和死亡率差异的种族相关基因表达差异和多态性。在确定了关键的表达和序列差异后，目标3将研究这些基因及其在乳腺细胞系中的通路，以评估它们对正常形态发生和癌症进展的影响。该项目的数据将确定种族相关乳腺癌死亡率的新生物学靶点，并确定种族相关基因表达差异促进非裔美国妇女肿瘤进展的机制。