Vissers Tessa A C M, Piek Leonie, Patuleia Susana I S, Duinmeijer Aafke J, Bakker Marije F, van der Wall Elsken, van Diest Paul J, van Gils Carla H, Moelans Cathy B
Department of Pathology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
Department of Medical Oncology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
Cancers (Basel). 2022 Aug 5;14(15):3805. doi: 10.3390/cancers14153805.
High mammographic density (MD) is associated with an increased risk of breast cancer, however the underlying mechanisms are largely unknown. This research aimed to identify microRNAs (miRNAs) that play a role in the development of extremely dense breast tissue. In the discovery phase, 754 human mature miRNAs were profiled in 21 extremely high MD- and 20 very low MD-derived nipple aspirate fluid (NAF) samples from healthy women. In the validation phase, candidate miRNAs were assessed in a cohort of 89 extremely high MD and 81 very low MD NAF samples from healthy women. Independent predictors of either extremely high MD or miRNA expression were identified by logistic regression and linear regression analysis, respectively. mRNA targets and pathways were identified through miRTarBase, TargetScan, and PANTHER pathway analysis. Statistical analysis identified four differentially expressed miRNAs during the discovery phase. During the validation, linear regression ( = 0.029; fold change = 2.10) and logistic regression ( = 0.048; odds ratio = 1.38) showed that hsa-miR-29c-5p was upregulated in extremely high MD-derived NAF. Identified candidate mRNA targets of hsa-miR-29c-5p are CFLAR, DNMT3A, and PTEN. Further validation and exploration of targets and downstream pathways of has-miR-29c-5p will provide better insight into the processes involved in the development of high MD and in the associated increased risk of breast cancer.
乳腺钼靶高密度（MD）与乳腺癌风险增加相关，但其潜在机制大多未知。本研究旨在鉴定在极致密乳腺组织发育中起作用的微小RNA（miRNA）。在发现阶段，对来自健康女性的21份极高MD和20份极低MD来源的乳头抽吸液（NAF）样本中的754种人类成熟miRNA进行了分析。在验证阶段，对来自健康女性的89份极高MD和81份极低MD NAF样本队列中的候选miRNA进行了评估。分别通过逻辑回归和线性回归分析确定了极高MD或miRNA表达的独立预测因子。通过miRTarBase、TargetScan和PANTHER通路分析确定了mRNA靶标和通路。统计分析在发现阶段鉴定出四种差异表达的miRNA。在验证过程中，线性回归（P = 0.029；倍数变化 = 2.10）和逻辑回归（P = 0.048；比值比 = 1.38）表明，hsa-miR-29c-5p在极高MD来源的NAF中上调。已鉴定出hsa-miR-29c-5p的候选mRNA靶标为CFLAR、DNMT3A和PTEN。对has-miR-29c-5p的靶标和下游通路进行进一步验证和探索，将有助于更好地了解高MD发展过程以及相关乳腺癌风险增加所涉及的过程。
