Collagen Sequence Variants in Racial Disparities of Breast Cancer

乳腺癌种族差异中的胶原蛋白序列变异

• 批准号: 10058386
• 负责人: Peggi M Angel
• 金额: $ 55.26万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-03 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10058386
• 关键词: Affect; African American; Alcohols; American; Automobile Driving; Breast; Breast Cancer Early Detection; Breast Cancer Prevention; Breast Cancer Risk Factor; Breast cancer metastasis; COL1A1 gene; COL1A2 gene; Cells; Collagen; Collagen Fiber; Companions; Contraceptive Usage; Data; Data Reporting; Deposition; Diagnostic; Disease; Drug resistance; Environment; Ethnic Origin; European; Extracellular Matrix; Generations; Human; Hydroxylation; Incidence; Knowledge; Lead; Link; Mammary Gland Parenchyma; Mammary Neoplasms; Maps; Marital Status; Measurement; Measures; Microscopy; Minority; Modification; Neoplasm Metastasis; Oncogenic; Outcome; Peptides; Population; Post-Translational Protein Processing; Post-Translational Regulation; Proline; Proteomics; Race; Recurrence; Regulation; Risk; Risk Factors; Role; Signal Transduction; Site; Smoking; Socioeconomic Status; Stratification; Structure; Testing; The Cancer Genome Atlas; Time; Tissue Banks; Tissue Microarray; Tissue imaging; Tissues; Tumor-infiltrating immune cells; Variant; Woman; base; breast cancer progression; breast density; breast lumpectomy; cancer type; clinically relevant; density; early detection biomarkers; macrophage; malignant breast neoplasm; migration; mortality; novel; prevent; prognostic; racial disparity; receptor; second harmonic; socioeconomics; triple helix; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor progression; tumorigenic

In breast cancer, collagen re-alignment is predictive of subtype, outcome and recurrence with limited data on contribution to racial disparities. For African-American (AA) women, breast cancer mortality is higher than any other race/ethnicity, in spite of having lower incidence rates. A disproportionate number of African-American women are affected by aggressive metastatic triple negative breast cancer (TNBC) without significant knowledge of mechanisms driving this ancestry-dependent difference. Collagen processing is a primary feature of TNBC tumors with increases in tumor adjacent collagen deposition, altered tumor-stroma ratios, and re-alignment of collagen fibers at tumor borders leading to metastasis. However, a knowledge gap exists on understanding ancestry-dependent translational and post-translational mechanisms of the collagen structure in any breast cancer type progression. Our preliminary data reports, for the first time, that post-translational regulation of the collagen triple helical structure by hydroxylated prolines (HYP) is a defining mechanism of racial disparities in normal and TNBC tissue. Consequently, this proposal focuses on identifying ancestry-dependent translational and post-translational mechanisms of collagen re-alignment that can ultimately be used to predict and potentially prevent breast cancer metastasis in AA women. In Aim 1, we will define ancestry dependent post-translational HYP regulation of collagen sequences from low grade to invasive triple negative breast cancers. Novel technological platforms will be combined to measure collagen sequences from the tissue microenvironment with measurement of collagen fiber changes and immune infiltrate. In Aim 2, we will identify HYP post-translational regulation of collagen sequence variants in ancestry-mapped normal breast tissue stratified by density, socioeconomic status, marital status, contraceptive use, and risk factors of smoking and alcohol. We will further determine if collagen sequence variants can be used as a companion scoring metric for prediction of breast cancer risk. In Aim 3, ancestry-defined normal and metastatic human breast cells will be used to precisely trace ancestry dependent collagen processing and oncogenic signaling influenced by collagen sequence variants. This study will increase our understanding of racial disparities in metastatic collagen re-alignment, working to generate better ancestry-dependent biomarkers for earlier detection of breast cancer and limit mortality due to breast cancer in minority populations.

在乳腺癌中，胶原蛋白重新排列可预测亚型、结果和复发，但关于以下方面的数据有限： 造成种族不平等。对于非洲裔美国人（AA）女性，乳腺癌死亡率高于任何 其他种族/民族，尽管发病率较低。不成比例的非裔美国人 女性受侵袭性转移性三阴性乳腺癌（TNBC）的影响， 驱动这种祖先依赖性差异的机制。胶原蛋白加工是TNBC的主要特征 肿瘤邻近胶原沉积增加，肿瘤-间质比例改变， 肿瘤边缘的胶原纤维导致转移。然而，在理解上存在知识差距， 任何乳腺中胶原蛋白结构的祖先依赖性翻译和翻译后机制 癌症类型进展。我们的初步数据报告，第一次， 羟基化脯氨酸（HYP）的胶原三螺旋结构是种族差异的一种定义机制， 正常和TNBC组织。因此，本建议的重点是确定祖先依赖的翻译 以及胶原蛋白重新排列的翻译后机制，最终可用于预测和潜在 预防AA妇女的乳腺癌转移。在目标1中，我们将定义祖先依赖的翻译后 HYP对低级别至浸润性三阴性乳腺癌胶原序列的调节小说 技术平台将结合起来，从组织微环境中测量胶原蛋白序列， 胶原纤维变化和免疫浸润的测量。在目标2中，我们将鉴定HYP翻译后 通过密度分层的祖先映射的正常乳腺组织中胶原序列变体的调节， 社会经济状况、婚姻状况、避孕措施的使用以及吸烟和饮酒的风险因素。我们将进一步 确定胶原蛋白序列变体是否可以用作预测乳腺癌的伴随评分度量 癌症风险。在目标3中，将使用祖先定义的正常和转移性人类乳腺细胞来精确追踪 祖先依赖的胶原蛋白加工和致癌信号传导受胶原蛋白序列变异体的影响。 这项研究将增加我们对转移性胶原蛋白重新排列的种族差异的理解， 产生更好的血统依赖性生物标志物，用于早期检测乳腺癌并限制因乳腺癌而导致的死亡率 少数民族患乳腺癌