由IRCM 的Jean-Francois Coté博士領(lǐng)導(dǎo)的團隊在乳腺癌研究方面取得了一個重要的發(fā)現(xiàn),，這項研究的結(jié)果被發(fā)布在本周的PNAS上,。研究者們確定了,，一種名為DOCK1的蛋白質(zhì)可以作為潛在的靶標(biāo)用于減少乳腺癌患者的癌轉(zhuǎn)移,。
Coté's博士的實驗室一直對癌轉(zhuǎn)移的研究非常感興趣,，而乳腺癌是一種常常發(fā)生轉(zhuǎn)移的癌癥,。將近90%的乳腺癌患者都因為癌癥擴散而死,，因此,，理解這一危險過程的細(xì)胞和分子基礎(chǔ)機制是十分重要的。
IRCM細(xì)胞骨架組織和細(xì)胞遷移的研究中心的主任Coté博士說：“盡管在乳腺癌治療方面已經(jīng)取得了重要的進(jìn)展,，但是對于癌癥擴散的機制我們卻知之甚少,。我們正在試圖確定能夠調(diào)節(jié)癌轉(zhuǎn)移過程的蛋白質(zhì)，因為它們或許可以作為新的藥物靶標(biāo)，并與現(xiàn)有的方法相結(jié)合促進(jìn)治療的效果,。”
2個主要的癌癥亞型——HER-2+型和Basal-like型,，很容易轉(zhuǎn)移和復(fù)發(fā)，并最終導(dǎo)致患者的低生存率,。該調(diào)查以HER-2+(人類表皮生長因子受體2)型為研究對象,， 這代表了大約25%的乳腺癌病例。 HER2陽性腫瘤比其它類型的腫瘤更傾向于快速的發(fā)展和擴散,。
Coté's實驗室的博士生Mélanie Laurin是這篇文章的第一作者,，他解釋到：“通過研究HER2+乳腺癌小鼠模型，我們確定了DOCK1蛋白質(zhì)是癌轉(zhuǎn)移的一個重要的調(diào)控因子,。當(dāng)我們?nèi)コ诵∈笾械倪@一蛋白質(zhì)后,，乳腺癌的肺轉(zhuǎn)移大大減少了。我們還發(fā)現(xiàn),，DOCK1蛋白質(zhì)有助于腫瘤的生長,。”
Coté小組的合作者、IRCM 的Benjamin Haibe-Kains博士補充說：“為了證明DOCK1的表達(dá)與乳腺癌預(yù)后之間的關(guān)系,，我們對包含患者基因信息的幾個數(shù)據(jù)庫進(jìn)行了分析,。我們確實發(fā)現(xiàn)，在HER-2+型或Basal-like型乳腺癌中,，高水平的DOCK1與較差的預(yù)后以及疾病的復(fù)發(fā)有關(guān),。”
“我們的工作確定了乳腺癌惡化到轉(zhuǎn)移階段所必需的一個新分子，這樣我們就確定了可能停止癌轉(zhuǎn)移發(fā)展的新標(biāo)記物,。這些結(jié)果將最終指導(dǎo)開發(fā)新的藥物來限制乳腺癌轉(zhuǎn)移的發(fā)展,，進(jìn)而改善患者的預(yù)后。”
加拿大癌癥協(xié)會的科學(xué)交流顧問Melody Enguix說：“我們很榮幸能夠資助這項研究,。該發(fā)現(xiàn)為我們理解如何停止乳腺癌的轉(zhuǎn)移提供了重要的基礎(chǔ),。”(生物谷Bioon.com)
doi: 10.1073/pnas.1213050110
PMC:
PMID:
Rac-specific guanine nucleotide exchange factor DOCK1 is a critical regulator of HER2-mediated breast cancer metastasis
Mélanie Laurin, Jennifer Huber, Ariane Pelletier, Tarek Houalla, Morag Park, Yoshinori Fukui, Benjamin Haibe-Kains, William J. Muller, and Jean-Francois Coté.
Progression of solid tumors to the metastatic stage is accountable for the majority of cancer-related deaths. Further understanding of the molecular mechanisms governing metastasis is essential for the development of antimetastatic regimens. Here, we aimed to identify Rac activators that could promote metastasis downstream of human epithelial growth factor receptor 2 (HER2). We investigated if Dedicator of Cytokinesis 1 (DOCK1), based on its evolutionarily conserved role in receptor tyrosine kinases (RTKs)-mediated Rac activation and cell invasion, could be a regulator of metastasis. We report that high expression of DOCK1 in HER2+ and basal breast cancer subtypes inversely correlates with human patients’ survival. Mechanistically, DOCK1 interacts with HER2 and promotes HER2-induced Rac activation and cell migration. To gain further insight, we developed a HER2 breast cancer mouse model with mammary-gland–specific inactivation of DOCK1. In this in vivo model, a significant decrease in tumor growth and metastasis in lungs was found in animals where DOCK1 is inactivated. Furthermore, we found that DOCK1 is required for maximal activation of two HER2 effectors, c-JUN and STAT3. Using an unbiased gene profiling approach, we identified a mammary tumor DOCK1-associated gene signature enriched for genes implicated in response to IFN type I. This analysis revealed a unique set of genes, including Receptor Transporter Protein 4 (RTP4) and STAT1, for which the expression levels can be used to independently predict breast cancer outcome in HER2+ patients. Our work demonstrates DOCK1–Rac signaling as an HER2 effector pathway essential for HER2-mediated breast cancer progression to metastasis and offers a therapeutic opportunity to limit the spread of metastatic breast cancers.
