Although recurrent cancers are often aggressive, little is known about the intracellular events required for cancer recurrences. Due to this lack of mechanistic information, there is no test to predict cancer recurrences or non-recurrences during early stages of disease. In this retrospective study, we use ductal carcinoma in situ (DCIS) of the breast as a framework to better understand the mechanism of cancer recurrences using patient outcomes as the physiological observable. Conventional pathology slides were labeled with anti-phosphofructokinase type L (PFKL) and anti-phosphofructokinase/fructose-2,6-bisphosphatase type 4 (PFKFB4) reagents. PFKL and PFKFB4 were found in ductal epithelial cell nucleoli from DCIS samples of women who did not experience a cancer recurrence. In contrast, PFKL and PFKFB4 may be found near the plasma membrane in samples from patients who will develop recurrent cancer. Using machine learning to predict patient outcomes, holdout studies of individual patient micrographs for the three biomarkers PFKL, PFKFB4, and phosphorylated GLUT1 demonstrated 38.6% true negatives, 49.5% true positives, 11.9% false positives and 0% false negatives (N=101). A sub-population of recurrent samples demonstrated PFKL, PFKFB4, and phosphorylated glucose transporter 1 accumulation at the apical surface of epithelial cells, suggesting that carbohydrates can be harvested from the ducts' luminal spaces as an energy source. We suggest that PFK isotype patterns are metabolic switches representing key mechanistic steps of recurrences. Furthermore, PFK enzyme patterns within epithelial cells contribute to an accurate diagnostic test to classify DCIS patients as high or low recurrence risk.

中文翻译：

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上皮细胞内磷酸果糖激酶的重新定位是乳腺癌复发前的一个新事件，可准确预测患者预后

尽管复发性癌症通常具有侵袭性，但对癌症复发所需的细胞内事件知之甚少。由于缺乏机械信息，没有测试来预测疾病早期阶段的癌症复发或不复发。在这项回顾性研究中，我们使用乳腺导管原位癌 (DCIS) 作为框架，以使用患者结果作为生理可观察结果更好地了解癌症复发的机制。常规病理切片用 L 型抗磷酸果糖激酶 (PFKL) 和抗磷酸果糖激酶/4 型果糖-2,6-双磷酸酶 (PFKFB4) 试剂标记。在未经历癌症复发的女性 DCIS 样本的导管上皮细胞核仁中发现了 PFKL 和 PFKFB4。相比之下，PFKL 和 PFKFB4 可以在来自将发展为复发性癌症的患者的样本中的质膜附近发现。使用机器学习来预测患者结果，对三种生物标志物 PFKL、PFKFB4 和磷酸化 GLUT1 的个体患者显微照片的坚持研究表明 38.6% 的真阴性、49.5% 的真阳性、11.9% 的假阳性和 0% 的假阴性 (N=101) . 重复样本的一个亚群表明 PFKL、PFKFB4 和磷酸化葡萄糖转运蛋白 1 在上皮细胞的顶端表面积累，这表明碳水化合物可以从导管的腔内空间作为能量来源收集。我们建议 PFK 同种型模式是代表复发的关键机制步骤的代谢开关。此外，