The integrin alpha(v)beta(3-5) ligand MFG-E8 is a p63/p73 target gene in triple-negative breast cancers but exhibits suppressive functions in ER(+) and erbB2(+) breast cancers.
The integrin alpha(v)beta(3-5) ligand MFG-E8 is a p63/p73 target gene in triple-negative breast cancers but exhibits suppressive functions in ER(+) and erbB2(+) breast cancers.
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DOI：
10.1158/0008-5472.can-10-1471
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Schmidt EV
中科院分区：
文献类型：
--
作者：
Yang C;Hayashida T;Forster N;Li C;Shen D;Maheswaran S;Chen L;Anderson KS;Ellisen LW;Sgroi D;Schmidt EV
从浸润前病变到浸润性癌的进展是导致乳腺癌死亡的关键步骤。我们通过激光捕获显微切割（LCM）组织的微阵列分析确定了乳脂球EGF因子8（MFG-E8）的下调是乳腺癌进展的一个因素。我们首先在转基因乳腺肿瘤模型中鉴定了MFG-E8在浸润性病变中的下调，这在与患者匹配的正常组织相比的LCM分离的人浸润性导管癌中得到证实。雌激素受体（ER）阳性病例中MFG-E8表达的原位分析证实了其在乳腺癌进展过程中的下调，并且小的抑制性MFG-E8 RNA加速了ER+乳腺癌细胞增殖。MFG-E8在erbB 2+人类癌症中也减少，并且缺乏MFG-E8的erbB 2转基因小鼠显示加速的肿瘤形成。相比之下，MFG-E8表达在三阴性（ER-、PgR-、erbB 2-）乳腺癌、细胞系和患者血清中以高水平存在。敲除、ChIP和报告基因测定均显示p63调节MFG-E8表达，并且MFG-E8敲除使三阴性乳腺癌对顺铂治疗敏感。综上所述，我们的结果表明，MFG-E8作为p63通路的靶基因在三阴性乳腺癌中表达，但可能在ER+和erbB 2+乳腺癌中起抑制作用。其作为血清生物标志物的潜在用途，有助于三阴性乳腺癌的发病机制，敦促继续评估其差异功能。
The progression from preinvasive lesion to invasive carcinoma is a critical step contributing to breast cancer lethality. We identified down-regulation of milk fat globule-EGF factor 8 (MFG-E8) as a contributor to breast cancer progression using microarray analysis of laser capture microdissected (LCM) tissues. We first identified MFG-E8 down-regulation in invasive lesions in transgenic mammary tumor models, which were confirmed in LCM-isolated human invasive ductal carcinomas compared with patient-matched normal tissues. In situ analyses of MFG-E8 expression in estrogen receptor (ER) positive cases confirmed its down-regulation during breast cancer progression and small inhibitory MFG-E8 RNAs accelerated ER+ breast cancer cell proliferation. MFG-E8 also decreased in erbB2+ human cancers and erbB2 transgenic mice lacking MFG-E8 showed accelerated tumor formation. In contrast, MFG-E8 expression was present at high levels in triple negative (ER-, PgR-, erbB2-) breast cancers, cell lines and patient sera. Knockdown, ChIP and reporter assays all showed that p63 regulates MFG-E8 expression, and MFG-E8 knockdowns sensitized triple negative breast cancers to cisplatin treatment. Taken together, our results show that MFG-E8 is expressed in triple negative breast cancers as a target gene of the p63 pathway, but may serve a suppressive function in ER+ and erbB2+ breast cancers. Its potential use as a serum biomarker that contributes to the pathogenesis of triple negative breast cancers urges continued evaluation of its differential functions.