Presence of anaplastic lymphoma kinase in inflammatory breast cancer.
Presence of anaplastic lymphoma kinase in inflammatory breast cancer.
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DOI：
10.1186/2193-1801-2-497
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Cristofanilli M
中科院分区：
文献类型：
--
作者：
Robertson FM;Petricoin Iii EF;Van Laere SJ;Bertucci F;Chu K;Fernandez SV;Mu Z;Alpaugh K;Pei J;Circo R;Wulfkuhle J;Ye Z;Boley KM;Liu H;Moraes R;Zhang X;Demaria R;Barsky SH;Sun G;Cristofanilli M
尽管炎性乳腺癌（IBC）被认为是局部晚期乳腺癌中最具转移性的一种，但其独特的临床表现和加速转移的分子基础尚不清楚。逆相蛋白阵列显示，在临床前IBC模型中，受体酪氨酸激酶、间变性淋巴瘤激酶（ALK）和生化连接的下游信号分子包括JAK1/STAT3、AKT、mTor、PDK1和AMPKβ被激活。为了评估ALK在IBC中的临床相关性，使用FDA批准的ALK基因异常诊断测试对25例IBC患者的肿瘤进行了分析。这些研究表明，20/25（80%）的患者ALK拷贝数增加，ALK基因扩增水平低，或ALK基因表达，ALK改变在基底样IBC中普遍存在。25例患者中有1例被确定为EML4-ALK易位。通过使用TGCA数据库和我们新开发的79个IBC样基因标记对479个乳腺肿瘤进行分析，证明了具有IBC特征的基底样乳腺肿瘤中ALK拷贝数增加的普遍性。小分子双酪氨酸激酶cMET/ALK抑制剂Crizotinib （PF-02341066/Xalkori®，Pfizer Inc .）在IBC肿瘤细胞和FC-IBC01肿瘤异种移植模型（一种由ALK+ IBC患者分离的胸腔液细胞建立的新型IBC模型）中诱导细胞毒性（IC50 = 0.89 μM）和细胞凋亡，并消除pALK信号。基于这些研究，IBC患者目前正在评估是否存在ALK基因异常，如果符合条件，将被纳入评估ALK靶向治疗的临床试验。本文的在线版本（doi:10.1186/2193-1801-2-497）包含补充材料，可供授权用户使用。
Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPKβ in pre-clinical models of IBC. To evaluate the clinical relevance of ALK in IBC, analysis of 25 IBC patient tumors using the FDA approved diagnostic test for ALK genetic abnormalities was performed. These studies revealed that 20/25 (80%) had either increased ALK copy number, low level ALK gene amplification, or ALK gene expression, with a prevalence of ALK alterations in basal-like IBC. One of 25 patients was identified as having an EML4-ALK translocation. The generality of gains in ALK copy number in basal-like breast tumors with IBC characteristics was demonstrated by analysis of 479 breast tumors using the TGCA data-base and our newly developed 79 IBC-like gene signature. The small molecule dual tyrosine kinase cMET/ALK inhibitor, Crizotinib (PF-02341066/Xalkori®, Pfizer Inc), induced both cytotoxicity (IC50 = 0.89 μM) and apoptosis, with abrogation of pALK signaling in IBC tumor cells and in FC-IBC01 tumor xenograft model, a new IBC model derived from pleural effusion cells isolated from an ALK+ IBC patient. Based on these studies, IBC patients are currently being evaluated for the presence of ALK genetic abnormalities and when eligible, are being enrolled into clinical trials evaluating ALK targeted therapeutics. The online version of this article (doi:10.1186/2193-1801-2-497) contains supplementary material, which is available to authorized users.
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影响因子：
10.3
作者：
Hance, KW;Anderson, WF;Levine, PH
通讯作者：
Levine, PH
EML4-Alk融合转录本在胃肠道和乳腺癌中未发现。
影响因子：
8.8
作者：
Fukuyoshi, Y.;Inoue, H.;Kita, Y.;Utsunomiya, T.;Ishida, T.;Mori, M.
通讯作者：
Mori, M.
影响因子：
11.5
作者：
Van Laere, Steven J.;Ueno, Naoto T.;Bertucci, Francois
通讯作者：
Bertucci, Francois
影响因子：
5.2
作者：
Lin, Eva;Li, Li;Modrusan, Zora
通讯作者：
Modrusan, Zora
影响因子：
6.2
作者：
Cristofanilli, Massimo;Valero, Vicente;Hortobagyi, Gabriel N.
通讯作者：
Hortobagyi, Gabriel N.