PDF(Pubmed)
Abstract：
UNASSIGNED: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer. However, if left untreated, about 50% of DCIS progress. Preventing such a progression is of paramount importance. Cumulative evidence indicated that the mevalonate cascade, the core of cholesterol biosynthesis, contributes to the regulation of the Hippo signaling pathway providing the isoprenoids required for GTPase activation, the nuclear accumulation of the Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) coactivator, and the subsequent gene transcription and that the disruption of this cooperation associated with tumor progression.
UNASSIGNED: In this in silico study, we investigated whether such a disruption occurred already during the transformation of the normal mammary epithelium into DCIS. To this aim, we interrogated a publicly available dataset, and we explored the interrelationship of the genes involved in the de novo cholesterol biosynthesis and the association with those coding for the core components of the Hippo signaling pathway in a set of patient-matched samples of DCIS and corresponding histologically normal (HN) epithelium.
UNASSIGNED: Most genes involved in cholesterol biosynthesis were more expressed in DCIS than in the corresponding HN epithelium. This differential expression was associated with a substantial change in their correlation profile. In particular, 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGCR) and INSIG1 lost the positive association shown in the HN epithelium, and their negative association with LSS switched to a positive one. Also, GGPS1, which plays a crucial role in isoprenoids production, significantly changed its correlation profile. The positive association between GGPS1 and HMGCR or INSIG1 disappeared, whereas the positive association with SQLE, which drives the irreversible commitment to cholesterol, switched to a negative one in DCIS.
UNASSIGNED: Present findings corroborated the hypothesis that a dysfunctional mevalonate pathway possibly concurs with DCIS development by leading to abnormal production of isoprenoids, which in turn activate GTPases and promote YAP/TAZ nuclear translocation, and suggested the safe and low-cost treatment with statins as the possible winning strategy to contrast this metabolic dysfunction.
UNASSIGNED: In this in silico study, we investigated whether such a disruption occurred already during the transformation of the normal mammary epithelium into DCIS. To this aim, we interrogated a publicly available dataset, and we explored the interrelationship of the genes involved in the de novo cholesterol biosynthesis and the association with those coding for the core components of the Hippo signaling pathway in a set of patient-matched samples of DCIS and corresponding histologically normal (HN) epithelium.
UNASSIGNED: Most genes involved in cholesterol biosynthesis were more expressed in DCIS than in the corresponding HN epithelium. This differential expression was associated with a substantial change in their correlation profile. In particular, 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGCR) and INSIG1 lost the positive association shown in the HN epithelium, and their negative association with LSS switched to a positive one. Also, GGPS1, which plays a crucial role in isoprenoids production, significantly changed its correlation profile. The positive association between GGPS1 and HMGCR or INSIG1 disappeared, whereas the positive association with SQLE, which drives the irreversible commitment to cholesterol, switched to a negative one in DCIS.
UNASSIGNED: Present findings corroborated the hypothesis that a dysfunctional mevalonate pathway possibly concurs with DCIS development by leading to abnormal production of isoprenoids, which in turn activate GTPases and promote YAP/TAZ nuclear translocation, and suggested the safe and low-cost treatment with statins as the possible winning strategy to contrast this metabolic dysfunction.
摘要：
■导管原位癌（DCIS）是浸润性乳腺癌的非强制性前体。然而,如果不及时治疗，约50%的DCIS进展。防止这种进展至关重要。累积证据表明甲羟戊酸级联，胆固醇生物合成的核心，有助于调节Hippo信号通路，提供GTP酶激活所需的类异戊二烯，Yes相关蛋白（YAP）/转录共激活因子与PDZ结合基序（TAZ）共激活因子的核积累，以及随后的基因转录以及这种合作的破坏与肿瘤进展有关。
■在这项计算机模拟研究中，我们调查了在正常乳腺上皮转化为DCIS的过程中是否已经发生了这种破坏.为了这个目标,我们询问了一个公开的数据集，我们在一组患者匹配的DCIS和相应的组织学正常（HN）上皮样本中，探索了参与从头胆固醇生物合成的基因之间的相互关系，以及与编码Hippo信号通路核心成分的基因之间的关联。
■大多数参与胆固醇生物合成的基因在DCIS中的表达高于相应的HN上皮。这种差异表达与它们的相关性谱的实质性变化有关。特别是,3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）和INSIG1失去了HN上皮中显示的正相关，它们与LSS的负相关转变为正相关。此外，GGPS1在类异戊二烯生产中起着至关重要的作用，显著改变了其相关性。GGPS1和HMGCR或INSIG1之间的正相关消失，而与SQLE的正相关，这推动了对胆固醇的不可逆转的承诺，在DCIS中切换为负数。
■目前的发现证实了以下假设：功能失调的甲羟戊酸途径可能通过导致类异戊二烯的异常产生而与DCIS的发展相一致。进而激活GTP酶并促进YAP/TAZ核易位，并建议他汀类药物的安全和低成本治疗作为对比这种代谢功能障碍的可能的获胜策略。
■在这项计算机模拟研究中，我们调查了在正常乳腺上皮转化为DCIS的过程中是否已经发生了这种破坏.为了这个目标,我们询问了一个公开的数据集，我们在一组患者匹配的DCIS和相应的组织学正常（HN）上皮样本中，探索了参与从头胆固醇生物合成的基因之间的相互关系，以及与编码Hippo信号通路核心成分的基因之间的关联。
■大多数参与胆固醇生物合成的基因在DCIS中的表达高于相应的HN上皮。这种差异表达与它们的相关性谱的实质性变化有关。特别是,3-羟基-3-甲基戊二酰辅酶A还原酶（HMGCR）和INSIG1失去了HN上皮中显示的正相关，它们与LSS的负相关转变为正相关。此外，GGPS1在类异戊二烯生产中起着至关重要的作用，显著改变了其相关性。GGPS1和HMGCR或INSIG1之间的正相关消失，而与SQLE的正相关，这推动了对胆固醇的不可逆转的承诺，在DCIS中切换为负数。
■目前的发现证实了以下假设：功能失调的甲羟戊酸途径可能通过导致类异戊二烯的异常产生而与DCIS的发展相一致。进而激活GTP酶并促进YAP/TAZ核易位，并建议他汀类药物的安全和低成本治疗作为对比这种代谢功能障碍的可能的获胜策略。
