Collagen Sequence Variants in Racial Disparities of Breast Cancer

在乳腺癌中，胶原蛋白重排可以预测亚型、预后和复发，但数据有限 对种族差异的贡献。对于非裔美国人(AA)女性来说，乳腺癌的死亡率比任何 其他种族/族裔，尽管发病率较低。数量不成比例的非裔美国人 女性在不知情的情况下患上侵袭性转移性三阴性乳腺癌 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 肿瘤周围胶原沉积增加，肿瘤间质比改变，肿瘤重新排列 肿瘤边缘的胶原纤维导致转移。然而，在理解上存在着知识鸿沟 任何乳房中胶原结构的祖先依赖的翻译和翻译后机制 癌症类型进展。我们的初步数据首次报告，翻译后对 羟基脯氨酸的胶原三螺旋结构(HYP)是人类种族差异的一种定义机制 正常组织和TNBC组织。因此，这一建议侧重于确定依赖于祖先的翻译 和翻译后胶原蛋白重新排列的机制，最终可以用来预测和潜在地 预防再障妇女的乳腺癌转移。在目标1中，我们将定义依赖祖先的后翻译 从低度恶性到浸润性三阴性乳腺癌的胶原序列的Hyp调节。小说 技术平台将结合在一起，测量组织微环境中的胶原序列 测定胶原纤维变化及免疫浸润情况。在目标2中，我们将确定HYP翻译后 按密度分层的祖先图谱正常乳腺组织中胶原序列变异的调节， 社会经济状况、婚姻状况、避孕措施的使用以及吸烟和酗酒的危险因素。我们将进一步 确定胶原序列变异体是否可以作为乳房预测的伴随评分指标 癌症风险。在目标3中，祖先定义的正常和转移的人类乳腺细胞将被用来精确追踪 依赖祖先的胶原蛋白加工和致癌信号受胶原蛋白序列变异的影响。 这项研究将增加我们对转移性胶原蛋白重新排列中的种族差异的理解，致力于 产生更好的祖先依赖的生物标记物，以早期检测乳腺癌，并限制因以下原因而导致的死亡率 少数族裔人群中的乳腺癌。

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.