Rujchanarong Denys, Scott Danielle, Park Yeonhee, Brown Sean, Mehta Anand S, Drake Richard, Sandusky George E, Nakshatri Harikrishna, Angel Peggi M
Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Bruker-MUSC Center of Excellence, Clinical Glycomics, Medical University of South Carolina, Charleston, SC, United States.
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, United States.
Front Oncol. 2022 Jun 27;12:876651. doi: 10.3389/fonc.2022.876651. eCollection 2022.
A primary difference between black women (BW) and white women (WW) diagnosed with breast cancer is aggressiveness of the tumor. Black women have higher mortalities with similar incidence of breast cancer compared to other race/ethnicities, and they are diagnosed at a younger age with more advanced tumors with double the rate of lethal, triple negative breast cancers. One hypothesis is that chronic social and economic stressors result in ancestry-dependent molecular responses that create a tumor permissive tissue microenvironment in normal breast tissue. Altered regulation of N-glycosylation of proteins, a glucose metabolism-linked post-translational modification attached to an asparagine (N) residue, has been associated with two strong independent risk factors for breast cancer: increased breast density and body mass index (BMI). Interestingly, high body mass index (BMI) levels have been reported to associate with increases of cancer-associated N-glycan signatures. In this study, we used matrix assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) to investigate molecular pattern changes of N-glycosylation in ancestry defined normal breast tissue from BW and WW with significant 5-year risk of breast cancer by Gail score. N-glycosylation was tested against social stressors including marital status, single, education, economic status (income), personal reproductive history, the risk factors BMI and age. Normal breast tissue microarrays from the Susan G. Komen tissue bank (BW=43; WW= 43) were used to evaluate glycosylation against socioeconomic stress and risk factors. One specific N-glycan (2158 m/z) appeared dependent on ancestry with high sensitivity and specificity (AUC 0.77, Brown/Wilson p-value<0.0001). Application of a linear regression model with ancestry as group variable and socioeconomic covariates as predictors identified a specific N-glycan signature associated with different socioeconomic stresses. For WW, household income was strongly associated to certain N-glycans, while for BW, marital status (married and single) was strongly associated with the same N-glycan signature. Current work focuses on understanding if combined N-glycan biosignatures can further help understand normal breast tissue at risk. This study lays the foundation for understanding the complexities linking socioeconomic stresses and molecular factors to their role in ancestry dependent breast cancer risk.
被诊断患有乳腺癌的黑人女性（BW）和白人女性（WW）之间的一个主要差异在于肿瘤的侵袭性。与其他种族/族裔相比，黑人女性在乳腺癌发病率相似的情况下死亡率更高，而且她们被诊断出患有乳腺癌时年龄更小，肿瘤更晚期，致死性三阴性乳腺癌的发病率是其他群体的两倍。一种假说认为，长期的社会和经济压力源会导致依赖祖先的分子反应，从而在正常乳腺组织中形成有利于肿瘤生长的组织微环境。蛋白质N-糖基化的调节改变是一种与葡萄糖代谢相关的翻译后修饰，连接在天冬酰胺（N）残基上，它与乳腺癌的两个强烈独立风险因素有关：乳腺密度增加和体重指数（BMI）。有趣的是，据报道高体重指数（BMI）水平与癌症相关的N-聚糖特征增加有关。在本研究中，我们使用基质辅助激光解吸/电离（MALDI）成像质谱（IMS）来研究根据祖先定义的正常乳腺组织中N-糖基化的分子模式变化，这些乳腺组织来自根据盖尔评分有显著5年乳腺癌风险的黑人女性和白人女性。针对包括婚姻状况、单身、教育程度、经济状况（收入）、个人生育史、风险因素BMI和年龄在内的社会压力源对N-糖基化进行了测试。来自苏珊·G·科门组织库的正常乳腺组织微阵列（黑人女性=43例；白人女性=43例）用于评估糖基化与社会经济压力和风险因素的关系。一种特定的N-聚糖（2158 m/z）似乎依赖于祖先，具有高敏感性和特异性（曲线下面积0.77，布朗/威尔逊p值<0.0001）。以祖先为分组变量、社会经济协变量为预测因子应用线性回归模型，确定了一种与不同社会经济压力相关的特定N-聚糖特征。对于白人女性，家庭收入与某些N-聚糖密切相关，而对于黑人女性，婚姻状况（已婚和单身）与相同的N-聚糖特征密切相关。目前的工作重点是了解联合N-聚糖生物标志物是否能进一步帮助理解有风险的正常乳腺组织。这项研究为理解社会经济压力和分子因素之间的复杂联系奠定了基础，这些因素在依赖祖先的乳腺癌风险中发挥着作用。
