BACKGROUND Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERα+) and represent risk indicators and/or precursor lesions to low grade ERα+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. METHODS In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues. RESULTS A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERα, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels. CONCLUSIONS The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.

中文翻译：

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非典型乳腺增生的基因表达特征和 SFRP1 的调控。

背景 非典型乳腺增生 (AH) 有 10 年进展为浸润性癌的风险，估计为 4-7%，患乳腺癌的总体风险增加了约 4 倍。AH 病变是雌激素受体 α 阳性 (ERα+)，代表风险指标和/或低级别 ERα+ 肿瘤的前体病变。因此，AH 病变的分子谱提供了对乳腺上皮最早变化的见解，使其易受致癌转化的影响。方法 在这项研究中，选择了在 2 年随访之前或之内被诊断为导管或小叶 AH，但没有乳腺癌的女性。显微解剖来自患者的配对 AH 和组织学上正常的良性 (HNB) 组织。RNA 被分离、线性扩增、标记、并与全转录组微阵列杂交以确定基因表达谱。AH 和 HNB 之间差异表达的基因使用配对分析进行鉴定。使用 AGNES 和 PAM 方法定义区分 AH 和 HNB 的基因表达特征。使用乳腺上皮细胞系、正常乳腺组织和小鼠组织的外植体培养物研究了基因网络的调节。结果 在 81% 的病例中，一个 99 基因特征区分了组织学上正常的组织和 AH 组织。网络分析通过 ERα、表皮生长因子受体和雄激素受体确定了信号传导的协调变化，这些变化与小叶和导管 AH 的发展有关。SFRP1 表达的降低在 AH 中也始终较低。在 76N-Tert 细胞中敲除 SFRP1 导致 13 个基因的表达改变，与在 AH 中观察到的相似。在缺乏 Sfrp1 的小鼠的组织中也观察到了 SFRP1 调节的网络。SFRP1 在 MCF7 细胞中的重新表达为 SFRP1 调节的网络提供了进一步的支持。用 rSFRP1 处理乳房外植体培养物会抑制雌激素诱导的孕激素受体水平。结论 在导管和小叶 AH 中均观察到基因表达的改变，这表明易患 AH 的共同潜在机制。SFRP1 表达的缺失是 AH 转录谱的重要调节因子，它驱动先前未识别的变化，影响对雌激素和可能的其他途径的反应。基因特征和通路提供了对导致 AH 乳腺病变的改变的见解。