Ductal carcinoma in situ (DCIS), which accounts for one out of every five new breast cancer diagnoses, will progress to potentially lethal invasive ductal carcinoma (IDC) in about 50% of cases. Vitamin D compounds have been shown to inhibit progression to IDC in the MCF10DCIS model. This inhibition appears to involve a reduction in the cancer stem cell–like population in MCF10DCIS tumors. To identify genes that are involved in the vitamin D effects, a global transcriptomic analysis was undertaken of MCF10DCIS cells grown in mammosphere cultures, in which cancer stem–like cells grow preferentially and produce colonies by self-renewal and maturation, in the presence and absence of 1α25(OH)2D3 and a vitamin D analog, BXL0124. Using next-generation RNA-sequencing, we found that vitamin D compounds downregulated genes involved in maintenance of breast cancer stem–like cells (e.g., GDF15), epithelial–mesenchymal transition, invasion, and metastasis (e.g., LCN2 and S100A4), and chemoresistance (e.g., NGFR, PPP1R1B, and AGR2), while upregulating genes associated with a basal-like phenotype (e.g., KRT6A and KRT5) and negative regulators of breast tumorigenesis (e.g., EMP1). Gene methylation status was analyzed to determine whether the changes in expression induced by vitamin D compounds occurred via this mechanism. Ingenuity pathway analysis was performed to identify upstream regulators and downstream signaling pathway genes differentially regulated by vitamin D, including TP63 and vitamin D receptor –mediated canonical pathways in particular. This study provides a global profiling of changes in the gene signature of DCIS regulated by vitamin D compounds and possible targets for chemoprevention of DCIS progression to IDC in patients.

中文翻译：

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转录组分析：维生素 D 化合物对乳腺导管原位癌干性的调节

导管原位癌 (DCIS) 占新乳腺癌诊断的五分之一，在大约 50% 的病例中将发展为潜在致命的浸润性导管癌 (IDC)。在 MCF10DCIS 模型中，维生素 D 化合物已被证明可抑制进展为 IDC。这种抑制似乎涉及 MCF10DCIS 肿瘤中癌症干细胞样群的减少。为了鉴定与维生素 D 效应有关的基因，对在乳腺球培养物中生长的 MCF10DCIS 细胞进行了全球转录组学分析，其中癌症干细胞样细胞优先生长并通过自我更新和成熟产生集落，在存在和不存在的情况下1α25(OH)2D3 和维生素 D 类似物 BXL0124。使用下一代 RNA 测序，我们发现维生素 D 化合物下调参与维持乳腺癌干细胞样细胞（如 GDF15）、上皮间质转化、侵袭和转移（如 LCN2 和 S100A4）和化学抗性（如 NGFR、PPP1R1B、和 AGR2)，同时上调与基底样表型相关的基因（例如 KRT6A 和 KRT5）和乳腺肿瘤发生的负调节因子（例如 EMP1）。分析基因甲基化状态以确定维生素 D 化合物诱导的表达变化是否通过这种机制发生。进行了独创性通路分析，以确定受维生素 D 差异调节的上游调节因子和下游信号通路基因，特别是 TP63 和维生素 D 受体介导的经典通路。