α-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration.
α-Tubulin acetylation elevated in metastatic and basal-like breast cancer cells promotes microtentacle formation, adhesion, and invasive migration.
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DOI：
10.1158/0008-5472.can-13-3563
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发表时间：
2015-01-01
期刊：
影响因子：
11.2
通讯作者：
Martin SS
中科院分区：
文献类型：
--
作者：
Boggs AE;Vitolo MI;Whipple RA;Charpentier MS;Goloubeva OG;Ioffe OB;Tuttle KC;Slovic J;Lu Y;Mills GB;Martin SS
乳腺癌的转移病例对该疾病的临床治疗提出了主要挑战，需要确定仍然需要的有效治疗策略。在这项研究中，我们报告说，α-微管蛋白乙酰化水平升高是乳腺癌转移潜力的充分原因。在悬浮细胞培养条件下，转移性乳腺癌细胞表现出沿着微触手突起延伸的高α-微管蛋白乙酰化水平。 α-微管蛋白上乙酰化位点的突变和这种翻译后修饰的酶促调节对微触手频率和悬浮肿瘤细胞的重新附着产生了显着影响。减少 α-微管蛋白乙酰化显着抑制迁移，但不影响增殖。在对来自患者的 140 多个匹配的原发性和转移性肿瘤的分析中，我们发现与原发性肿瘤相比，淋巴结转移中的乙酰化得以维持，并且在许多情况下有所增加。对超过 390 名患者样本的独立队列进行的蛋白质组学分析进一步记录了 α-微管蛋白乙酰化增加与基底样乳腺癌侵袭行为之间的关系，原发肿瘤中高强度 α-微管蛋白乙酰化的患者存在疾病进展和死亡风险增加的趋势。总而言之，我们的结果确定了乙酰化 α-微管蛋白水平与乳腺癌的侵袭性转移行为之间存在紧密相关性，这对乳腺癌患者简单预后生物标志物的定义具有潜在影响。
Metastatic cases of breast cancer pose the primary challenge in clinical management of this disease, demanding the identification of effective therapeutic strategies which remain wanting. In this study, we report that elevated levels of α-tubulin acetylation are a sufficient cause of metastatic potential in breast cancer. In suspended cell culture conditions, metastatic breast cancer cells exhibited high α-tubulin acetylation levels that extended along microtentacle protrusions. Mutation of the acetylation site on α-tubulin and enzymatic modulation of this post-translational modification exerted a significant impact on microtentacle frequency and the re-attachment of suspended tumor cells. Reducing α-tubulin acetylation significantly inhibited migration but did not affect proliferation. In an analysis of over 140 matched primary and metastatic tumors from patients, we found that acetylation was maintained and in many cases increased in lymph node metastases compared to primary tumors. Proteomic analysis of an independent cohort of over 390 patient specimens further documented the relationship between increased α-tubulin acetylation and the aggressive behaviors of basal-like breast cancers, with a trend toward increased risk of disease progression and death in patients with high intensity α-tubulin acetylation in primary tumors. Taken together, our results identify a tight correlation between acetylated α-tubulin levels and aggressive metastatic behavior in breast cancer, with potential implications for the definition of a simple prognostic biomarker in breast cancer patients.