Breast tumor heterogeneity is a major impediment to oncotherapy. Cancer cells undergo rapid clonal evolution, thereby acquiring significant growth and invasive advantages. The absence of specific markers of these high-risk populations precludes efficient therapeutic and diagnostic management of the disease. Given the critical function of tumor microenvironment in the oncogenic circuitry, we sought to determine the expression profile of the extracellular matrix oncoprotein, extradomain-B fibronectin (EDB-FN) in invasive breast cancer. Analyses of TCGA/GTEx databases and immunostaining of clinical samples found a significant overexpression of EDB-FN in breast tumors, which correlated with poor overall survival. Significant upregulation of EDB-FN was observed in invasive cell populations generated from relatively less invasive MCF7 and MDA-MB-468 cells by long-term TGF-β treatment and acquired chemoresistance. Treatment of the invasive cell populations with an AKT inhibitor (MK2206-HCl) reduced their invasive potential, with a concomitant decrease in their EDB-FN expression, partly through the phosphoAKT-SRp55 pathway. EDB-FN downregulation, with direct RNAi of EDB-FN or indirectly through RNAi of SRp55, also resulted in reduced motility of the invasive cell populations, validating the correlation between EDB-FN expression and invasion of breast cancer cells. These data establish EDB-FN as a promising molecular marker for non-invasive therapeutic surveillance of aggressive breast cancer.

中文翻译：

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Extradomain-B纤连蛋白的过度表达与乳腺癌细胞的侵袭有关。

乳腺癌异质性是肿瘤治疗的主要障碍。癌细胞会经历快速的克隆进化，从而获得显着的生长和侵袭优势。这些高危人群缺乏特异性标志物，无法有效治疗和诊断疾病。考虑到肿瘤微环境在致癌电路中的关键功能，我们试图确定浸润性乳腺癌中细胞外基质癌蛋白，域外B纤连蛋白（EDB-FN）的表达谱。TCGA / GTEx数据库的分析和临床样品的免疫染色发现，乳腺肿瘤中EDB-FN明显过量表达，这与较差的总体生存率相关。通过长期TGF-β处理和获得性化学耐药性，在侵袭性较弱的MCF7和MDA-MB-468细胞产生的侵袭性细胞群体中观察到EDB-FN的显着上调。用AKT抑制剂（MK2206-HCl）处理侵袭性细胞群体会降低其侵袭潜能，同时其EDB-FN表达也会降低，部分是通过phosphoAKT-SRp55途径。EDB-FN的下调，通过EDB-FN的直接RNAi或通过SRp55的RNAi间接，也导致侵袭性细胞群体的运动性降低，从而验证了EDB-FN表达与乳腺癌细胞侵袭之间的相关性。这些数据将EDB-FN确立为侵略性乳腺癌的非侵入性治疗监测的有希望的分子标记。用AKT抑制剂（MK2206-HCl）处理侵袭性细胞群体会降低其侵袭潜能，同时其EDB-FN表达也会降低，部分是通过phosphoAKT-SRp55途径。EDB-FN的下调，通过EDB-FN的直接RNAi或通过SRp55的RNAi间接，也导致侵袭性细胞群体的运动性降低，从而验证了EDB-FN表达与乳腺癌细胞侵袭之间的相关性。这些数据将EDB-FN确立为对侵袭性乳腺癌进行非侵入性治疗监测的有希望的分子标记。用AKT抑制剂（MK2206-HCl）处理侵袭性细胞群体会降低其侵袭潜能，同时其EDB-FN表达也会降低，部分是通过phosphoAKT-SRp55途径。EDB-FN的下调，通过EDB-FN的直接RNAi或通过SRp55的RNAi间接，也导致侵袭性细胞群体的运动性降低，从而验证了EDB-FN表达与乳腺癌细胞侵袭之间的相关性。这些数据将EDB-FN确立为对侵袭性乳腺癌进行非侵入性治疗监测的有希望的分子标记。EDB-FN的直接RNAi或SRp55的RNAi间接引起的侵袭性细胞群运动性降低，验证了EDB-FN表达与乳腺癌细胞侵袭之间的相关性。这些数据将EDB-FN确立为对侵袭性乳腺癌进行非侵入性治疗监测的有希望的分子标记。EDB-FN的直接RNAi或SRp55的RNAi间接引起的侵袭性细胞群运动性降低，验证了EDB-FN表达与乳腺癌细胞侵袭之间的相关性。这些数据将EDB-FN确立为对侵袭性乳腺癌进行非侵入性治疗监测的有希望的分子标记。