Joglekar-Javadekar Madhura, Van Laere Steven, Bourne Michael, Moalwi Manal, Finetti Pascal, Vermeulen Peter B, Birnbaum Daniel, Dirix Luc Y, Ueno Naoto, Carter Monique, Rains Justin, Ramachandran Abhijit, Bertucci Francois, van Golen Kenneth L
The Laboratory for Cytoskeletal Physiology, Department of Biological Sciences, The University of Delaware, Newark, DE; The Center for Translational Cancer Research, The University of Delaware, Newark, DE.
Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.
Neoplasia. 2017 Jul;19(7):564-573. doi: 10.1016/j.neo.2017.03.002. Epub 2017 Jun 10.
Inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer due to its rapid onset and highly invasive nature. IBC carries 5- and 10-year disease-free survival rates of ~45% and <20%, respectively. Multiple studies demonstrate that in comparison with conventional breast cancer, IBC has a unique molecular identity. Here, we have identified platelet-derived growth factor receptor alpha (PDGFRA) as being uniquely expressed and active in IBC patient tumor cells.
Here we focus on characterizing and targeting PDGFRA in IBC. Using gene expression, we analyzed IBC patient samples and compared them with non-IBC patient samples. Further, using IBC cells in culture, we determined the effect of small molecules inhibitors in both in vitro and in vivo assays.
In IBC patients, we show more frequent PDGFRA activation signature than non-IBC samples. In addition, the PDGFRA activation signature is associated with shorter metastasis-free survival in both uni- and multivariate analyses. We also demonstrate that IBC cells express active PDGFRA. Finally, we show that PDGFRA targeting by crenolanib (CP-868-596), but not imatinib (STI571), two small molecule inhibitors, interferes with IBC cell growth and emboli formation in vitro and tumor growth in vivo.
Our data suggest that PDGFRA may be a promising target for therapy in IBC.
炎性乳腺癌（IBC）因其发病迅速且具有高度侵袭性，堪称最致命的乳腺癌形式。IBC的5年和10年无病生存率分别约为45%和低于20%。多项研究表明，与传统乳腺癌相比，IBC具有独特的分子特征。在此，我们已确定血小板衍生生长因子受体α（PDGFRA）在IBC患者肿瘤细胞中独特表达且具有活性。
在此，我们聚焦于IBC中PDGFRA的特征描述及靶向作用。利用基因表达，我们分析了IBC患者样本，并将其与非IBC患者样本进行比较。此外，利用培养的IBC细胞，我们在体外和体内试验中确定了小分子抑制剂的作用效果。
在IBC患者中，我们发现PDGFRA激活特征比非IBC样本更频繁。此外，在单变量和多变量分析中，PDGFRA激活特征均与无转移生存期较短相关。我们还证明IBC细胞表达活性PDGFRA。最后，我们表明，两种小分子抑制剂中，克伦洛尼（CP - 868 - 596）而非伊马替尼（STI571）靶向PDGFRA，可在体外干扰IBC细胞生长和栓子形成，并在体内抑制肿瘤生长。
我们的数据表明，PDGFRA可能是IBC治疗的一个有前景的靶点。
Zotero 插件
