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，胶原蛋白重新对齐可预测亚型，结局和复发，并且数据有限 对种族差异的贡献。对于非裔美国人（AA）妇女，乳腺癌死亡率高于任何 其他种族/种族，尽管发病率较低。非裔美国人数量不成比例 妇女在没有大量知识的情况下受到侵略性转移性三重阴性乳腺癌（TNBC）的影响 驱动这种依赖祖先差异的机制。胶原蛋白处理是TNBC的主要特征 肿瘤邻近胶原蛋白沉积，肿瘤 - 细胞瘤比的变化和重新对准的肿瘤 肿瘤边界处的胶原蛋白纤维导致转移。但是，知识差距存在于理解上 任何乳房中胶原蛋白结构的祖先依赖性翻译和翻译机制 癌症类型的进展。我们的初步数据报告是第一次的翻译后调节 通过羟基化脯氨酸（HYP）胶原蛋白三重螺旋结构是种族差异的定义机制 正常和TNBC组织。因此，该提案着重于识别依赖祖先的翻译 以及最终可用于预测和潜在的胶原蛋白重组的翻译后机制 预防AA女性乳腺癌转移。在AIM 1中，我们将定义依赖祖先的翻译后 从低年级到浸润性三重负乳腺癌的胶原蛋白序列的催眠调节。小说 技术平台将合并以测量来自组织微环境的胶原蛋白序列 测量胶原纤维变化和免疫浸润。在AIM 2中，我们将确定催眠后翻译 调节祖先映射的正常乳腺组织中胶原蛋白序列变异，该乳腺组织由密度分层， 社会经济地位，婚姻状况，避孕药使用以及吸烟和酒精的危险因素。我们将进一步 确定是否可以将胶原蛋白序列变体用作预测乳房的同伴评分度量 癌症风险。在AIM 3中，祖先定义的正常和转移性人类乳腺细胞将用于精确追踪 依赖性胶原蛋白处理和受胶原序列变体影响的致癌信号传导。 这项研究将提高我们对转移性胶原蛋白重组中种族差异的理解，并致力于 产生更好的祖先依赖性生物标志物，用于早期检测乳腺癌，并限制由于 少数族裔乳腺癌。