While the overall mortality for breast cancer has recently declined, management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and the lack of targeted therapies. Genomic profiling studies highlighted the high level of heterogeneity of this cancer, which comprises different subtypes with unique phenotypes and response to treatment. Platelet-derived growth factor receptor β (PDGFRβ) is an established mesenchymal/stem cell-specific marker in human glioblastoma and, as recently suggested, it may uniquely mark breast cancer cells with stem-like characteristics and/or that have undergone epithelial-mesenchymal transition.

Methods: Immunohistochemical analysis for PDGFRβ expression was performed on a human TNBC tissue microarray. Functional assays were conducted on mesenchymal-like TNBC cells to investigate the effect of a previously validated PDGFRβ aptamer on invasive cell growth in three-dimensional culture conditions, migration, invasion and tube formation. The aptamer was labeled with a near-infrared (NIR) dye and its binding specificity to PDGFRβ was assessed both in vitro (confocal microscopy and flow cytometry analyses) and in vivo (fluorescence molecular tomography in mice bearing TNBC xenografts). A mouse model of TNBC lung metastases formation was established and NIR-labeled PDGFRβ aptamer was used to detect lung metastases in mice untreated or intravenously injected with unlabeled aptamer.

Results: Here, we present novel data showing that tumor cell expression of PDGFRβ identifies a subgroup of mesenchymal tumors with invasive and stem-like phenotype, and propose a previously unappreciated role for PDGFRβ in driving TNBC cell invasiveness and metastases formation. We show that the PDGFRβ aptamer blocked invasive growth and migration/invasion of mesenchymal TNBC cell lines and prevented TNBC lung metastases formation. Further, upon NIR-labeling, the aptamer specifically bound to TNBC xenografts and detected lung metastases.

Conclusions: We propose PDGFRβ as a reliable biomarker of a subgroup of mesenchymal TNBCs with invasive and stem-like phenotype as well as the use of the PDGFRβ aptamer as a high efficacious tool for imaging and suppression of TNBC lung metastases. This study will allow for the significant expansion of the current repertoire of strategies for managing patients with more aggressive TNBC.

Keywords: aptamer, PDGFRβ, invasiveness, mesenchymal TNBC subtype, metastases.

尽管乳腺癌的总体死亡率最近有所下降，但三阴性乳腺癌（TNBC）的治疗仍然具有挑战性，因为其侵略性的临床行为和缺乏靶向疗法。基因组图谱研究强调了这种癌症的高度异质性，其包括具有独特表型和对治疗反应的不同亚型。血小板衍生的生长因子受体β（PDGFRβ）是人类胶质母细胞瘤中已建立的间充质/干细胞特异性标志物，并且如最近所建议的，它可以独特地标记具有干样特征和/或经历了上皮-间充质的乳腺癌细胞过渡。

方法：在人TNBC组织微阵列上进行PDGFRβ表达的免疫组织化学分析。在间充质样TNBC细胞上进行功能测定，以研究先前验证的PDGFRβ适体对三维培养条件下侵袭性细胞生长，迁移，侵袭和管形成的影响。适体用近红外（NIR）染料标记，并在体外（经孔镜和流式细胞术分析）和体内评估其与PDGFRβ的结合特异性（携带TNBC异种移植物的小鼠体内的荧光分子层析成像）。建立了TNBC肺转移形成小鼠模型，并使用NIR标记的PDGFRβ适体来检测未经治疗或静脉内注射未标记的适体的小鼠的肺转移。

结果：在这里，我们提出了新的数据，表明PDGFRβ的肿瘤细胞表达鉴定了具有侵袭性和茎样表型的间充质肿瘤的一个亚组，并提出了PDGFRβ在驱动TNBC细胞侵袭性和转移形成中未曾发挥的作用。我们表明，PDGFRβ适体阻止了间充质TNBC细胞系的侵袭性生长和迁移/侵袭，并阻止了TNBC肺转移的形成。此外，在进行NIR标记后，适体与TNBC异种移植物特异性结合并检测到肺转移。

结论：我们提出PDGFRβ是具有侵袭性和茎样表型的间充质TNBCs亚组的可靠生物标志物，以及将PDGFRβ适体用作成像和抑制TNBC肺转移的高效工具。这项研究将大大扩展当前管理更具侵略性TNBC患者的策略范围。

关键词：适体，PDGFRβ，侵袭性，间充质TNBC亚型，转移。