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: 10210243
• 负责人: Peggi M Angel
• 金额: $ 53.9万
• 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/10210243
• 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 Groups; Modification; Neoplasm Metastasis; Oncogenic; Outcome; Peptides; 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，但数据有限 种族差异的贡献。对于非裔美国 (AA) 女性来说，乳腺癌死亡率高于任何女性 其他种族/民族，尽管发病率较低。非洲裔美国人的比例不成比例 女性在不知情的情况下就受到侵袭性转移性三阴性乳腺癌 (TNBC) 的影响 驱动这种依赖于祖先的差异的机制。胶原蛋白加工是 TNBC 的主要特征 肿瘤邻近胶原沉积增加、肿瘤基质比率改变以及肿瘤基质重新排列 肿瘤边界处的胶原纤维导致转移。然而，在理解上存在知识差距 任何乳房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。我们的初步数据首次报告了翻译后调控 羟基化脯氨酸（HYP）的胶原蛋白三螺旋结构是种族差异的决定性机制 正常组织和 TNBC 组织。因此，该提案的重点是识别祖先依赖的翻译 和胶原蛋白重新排列的翻译后机制，最终可用于预测和潜在的 预防 AA 女性乳腺癌转移。在目标 1 中，我们将定义祖先依赖的翻译后 HYP 对胶原蛋白序列的调节，从低级别乳腺癌到侵袭性三阴性乳腺癌。小说 将结合技术平台来测量组织微环境中的胶原蛋白序列 测量胶原纤维变化和免疫浸润。在目标 2 中，我们将识别 HYP 翻译后 按密度分层的祖先映射的正常乳腺组织中胶原蛋白序列变异的调节， 社会经济状况、婚姻状况、避孕药具的使用以及吸烟和饮酒的危险因素。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房的伴随评分指标 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 受胶原蛋白序列变异影响的祖先依赖性胶原蛋白加工和致癌信号传导。 这项研究将增加我们对转移性胶原蛋白重新排列中种族差异的理解，致力于 产生更好的依赖于祖先的生物标志物，用于早期检测乳腺癌并限制因乳腺癌引起的死亡率 少数人群的乳腺癌。